Vaccines containing ribavirin and methods of use thereof

ABSTRACT

The present invention relates to compositions and methods for enhancing the effect of vaccines in animals, such as domestic, sport, or pet species, and humans. More particularly, the use of Ribavirin as an adjuvant to a vaccine protocol and compositions having Ribavirin and an antigen are described.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/705,547 having a filing date of Nov. 3, 2000, which claims thebenefit of priority of U.S. provisional patent application No.60/229,175, filed Aug. 29, 2000; both of which are hereby expresslyincorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to compositions and methods for enhancingthe effect of vaccines in animals, such as domestic, sport, or petspecies, and humans. More particularly, preferred embodiments concernthe use of Ribavirin as an adjuvant and compositions having Ribavirinand an antigen.

BACKGROUND OF THE INVENTION

The use of vaccines to prevent disease in humans, farm livestock, sportsanimals, and household pets is a common practice. Frequently, however,the antigen used in a vaccine is not sufficiently immunogenic to raisethe antibody titre to levels that are sufficient to provide protectionagainst subsequent challenge or to maintain the potential for mountingthese levels over extended time periods. Further, many vaccines arealtogether deficient in inducing cell-mediated immunity, which is aprimary immune defense against bacterial and viral infection. Aconsiderable amount of research is currently focussed on the developmentof more potent vaccines and ways to enhance the immunogenicity ofantigen-containing preparations. (See e.g., U.S. Pat. Nos. 6,056,961;6,060,068; 6,063,380; and Li et al., Science 288:2219-2222 (2000)).

Notorious among such “weak” vaccines are hepatitis B vaccines. Forexample, recombinant vaccines against hepatitis B virus such asGenhevacb (Pasteur Merieux Serums et Vaccines, 58, Avenue Leclerc 69007Lyon, France), Engerixb (Smith, Kline and Symbol French), andRecombivaxhb (Merck, Sharp, and Dhome) are effective only after at leastthree injections at 0, 30, and 60 or 180 days, followed by an obligatorybooster after one year. (Chedid et al., U.S. Pat. No. 6,063,380).Additionally, many subjects receiving these vaccines respond poorly, ifat all. Because many regions of the world are endemic for HBV infection,the poorly immunogenic character of existing HBV vaccines has become anextremely serious problem.

To obtain a stronger, humoral and/or cellular response, it is common toadminister a vaccine in a material that enhances the immune response ofthe patient to the antigen present in the vaccine. The most commonlyused adjuvants for vaccine protocols are oil preparations and alum.(Chedid et al., U.S. Pat. No. 6,063,380). A greater repertoire of safeand effective adjuvants is needed.

Nucleoside analogs have been widely used in anti-viral therapies due totheir capacity to reduce viral replication. (Hosoya et al., J. Inf.Dis., 168:641-646 (1993)). Ribavirin(1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a syntheticguanosine analog that has been used to inhibit RNA and DNA virusreplication. (Huffman et al., Antimicrob. Agents. Chemother., 3:235(1973); Sidwell et al., Science, 177:705 (1972)). Ribavirin has beenshown to be a competitive inhibitor of inositol mono-phosphate (IMP)dehydrogenase (IMPDH), which converts IMP to IMX (which is thenconverted to GMP). De Clercq, Anti viral Agents: characteristic activityspectrum depending on the molecular target with which they interact,Academic press, Inc., New York N.Y., pp. 1-55 (1993). Intracellularpools of GTP become depleted as a result of long term Ribavirintreatment.

In addition to antiviral activity, investigators have observed that afew guanosine analogs have an effect on the immune system. (U.S. Pat.Nos. 6,063,772 and 4,950,647). Ribavirin has been shown to inhibitfunctional humoral immune responses (Peavy et al., J. Immunol.,126:861-864 (1981); Powers et al., Antimicrob. Agents. Chemother.,22:108-114 (1982)) and IgE-mediated modulation of mast cell secretion.(Marquardt et al., J. Pharmacol. Exp. Therapeutics, 240:145-149 (1987)).Some investigators report that a daily oral therapy of Ribavirin has animmune modulating effect on humans and mice. (Hultgren et al., J. Gen.Virol., 79:2381-2391 (1998) and Cramp et al., Gastron. Enterol.,118:346-355 (2000)). Nevertheless, the current understanding of theeffects of Ribavirin on the immune system is in its infancy.

SUMMARY OF THE INVENTION

It has been discovered that Ribavirin can be used as an adjuvant toenhance an immune response to an antigen. Embodiments described hereininclude “strong” vaccine preparations that comprise an antigen andRibavirin. Generally, these preparations have an amount of Ribavirinthat is sufficient to enhance an immune response to the antigen. Otheraspects of the invention include methods of enhancing the immuneresponse of an animal, including a human, to an antigen. By oneapproach, for example, an animal in need of a potent immune response toan antigen is identified and then is provided an amount of Ribavirintogether with the antigen that is effective to enhance an immuneresponse in the animal. In some methods, the Ribavirin and the antigenare provided in combination and in others, the Ribavirin and the antigenare provided separately. Thus, several embodiments concern themanufacture and use of vaccine preparations having Ribavirin and anantigen.

Preferred vaccine compositions comprise Ribavirin and a hepatitis viralantigen. The antigen can be a peptide or nucleic acid-based (e.g., a RNAencoding a peptide antigen or a construct that expresses a peptideantigen when introduced to a subject). HBV antigens that are suitableinclude, for example, hepatitis B surface antigen (HBsAg), hepatitiscore antigen (HBcAg), hepatitis e antigen (HBeAg), and nucleic acidsencoding these molecules. Compositions having Ribavirin and an antigenfrom the hepatitis A virus (HAV) or Ribavirin and a nucleic acidencoding an antigen from HAV are also embodiments. Still further,compositions having Ribavirin and an antigen from the hepatitis C virus(HCV) or Ribavirin and a nucleic acid encoding an antigen from HCV areembodiments.

Furthermore, compositions having a mixture of the antigens above areembodiments of the present invention. For example, some compositionscomprise a HBV antigen, a HAV antigen, and Ribavirin or a HBV antigen, aHCV antigen, and Ribavirin or a HAV antigen, a HCV antigen, andRibavirin or a HBV antigen, a HAV antigen, a HCV antigen, and Ribavirin.Other embodiments comprise Ribavirin and a nucleic acid encoding amixture of the antigens described above. Some embodiments also includeother adjuvants, binders, emulsifiers, carriers, and fillers, as knownin the art, including, but not limited to, alum, oil, and othercompounds that enhance an immune response.

Preferred methods involve providing an animal in need with a sufficientamount of Ribavirin and a hepatitis viral antigen (e.g., HBV antigen,HAV antigen, HCV antigen a nucleic acid encoding one of these antigensor any combination thereof). Accordingly, one embodiment includesidentifying an animal in need of an enhanced immune response to ahepatitis viral antigen (e.g., an animal at risk or already infectedwith a hepatitis infection) and providing to said animal an amount ofRibavirin that is effective to enhance an immune response to thehepatitis viral antigen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the humoral response to 10 and 100 μgrecombinant Hepatitis C virus (HCV) non structural 3 protein (NS3), asdetermined by mean end point titres, when a single dose of 1 mg ofRibavirin was co-administered.

FIG. 2 is a graph showing the humoral response to 20 μg recombinantHepatitis C virus (HCV) non structural 3 protein (NS3), as determined bymean end point titres, when a single dose of 0.1, 1.0, or 10 mg ofRibavirin was co-administered.

FIG. 3 is a graph showing the effects of a single dose of 1 mg Ribavirinon NS3-specific lymph node proliferative responses, as determined by invitro recall responses.

DETAILED DESCRIPTION OF THE INVENTION

It has been discovered that compositions comprising Ribavirin and anantigen can boost an animal's immune response to the antigen. That is,Ribavirin can be used as an “adjuvant,” which for the purposes of thisdisclosure, refers to a compound that has the ability to enhance theimmune response to a particular antigen. Such adjuvant activity ismanifested by a significant increase in immune-mediated protectionagainst the antigen, and was demonstrated by an increase in the titer ofantibody raised to the antigen and an increase in proliferative T cellresponses.

Several vaccine preparations that comprise Ribavirin and an antigen aredescribed herein. Vaccine formulations containing Ribavirin can varyaccording to the amount of Ribavirin, the form of Ribavirin, and thetype of antigen. The antigen can be a peptide or a nucleic acid (e.g., aRNA encoding a peptide antigen or a construct that expresses a peptideantigen when introduced into a subject). Preferred vaccine formulationscomprise Ribavirin and a hepatitis viral antigen (e.g., HBV antigen, HAVantigen, HCV antigen, a nucleic acid encoding these molecules, or anycombination thereof).

Methods of enhancing the immune response of an animal, including humans,to an antigen are also described herein. One method, for example,involves identifying an animal in need of an enhanced immune response toan antigen and providing the animal the antigen and an amount ofRibavirin that is effective to enhance an immune response to theantigen. Preferred methods involve providing the animal in need withRibavirin and a hepatitis antigen (e.g., HBV antigen, HAV antigen, HCVantigen, a nucleic acid encoding these molecules, or any combinationthereof). The section below describes the manufacture of vaccines havingRibavirin and an antigen in greater detail.

Vaccines Containing Ribavirin

The vaccines comprise Ribavirin and an antigen and may contain otheringredients including, but not limited to, adjuvants, binding agents,excipients such as stabilizers (to promote long term storage),emulsifiers, thickening agents, salts, preservatives, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. These vaccinepreparations are suitable for treatment of animals either as apreventive measure to avoid a disease or condition or as a therapeuticto treat animals already afflicted with a disease or condition.

The vaccine compositions can be manufactured in accordance withconventional methods of galenic pharmacy to produce medicinal agents foradministration to animals, e.g., mammals including humans. Ribavirin canbe obtained from commercial suppliers (e.g., Sigma and ICN). Ribavirinand/or the antigen can be formulated into the vaccine with and withoutmodification. For example, the Ribavirin and/or antigen can be modifiedor derivatized to make a more stable molecule and/or a more potentadjuvant. By one approach, the stability of Ribavirin and/or an antigencan be enhanced by coupling the molecules to a support such as ahydrophilic polymer (e.g., polyethylene glycol).

Many more Ribavirin derivatives can be generated using conventionaltechniques in rational drug design and combinatorial chemistry. Forexample, Molecular Simulations Inc. (MSI), as well as many othersuppliers, provide software that allows one of skill to build acombinatorial library of organic molecules. The C2.Analog Builderprogram, for example, can be integrated with MSI's suite of Cerius2molecular diversity software to develop a library of Ribavirinderivatives that can be used with the embodiments described herein. (Seee.g., http://msi.com/life/products/cerius2/index.html, herein expresslyincorporated by reference in its entirety).

By one approach, the chemical structure of Ribavirin is recorded on acomputer readable media and is accessed by one or more modeling softwareapplication programs. The C2.Analog Builder program in conjunction withC2Diversity program allows the user to generate a very large virtuallibrary based on the diversity of R-groups for each substituentposition, for example. Compounds having the same structure as themodeled Ribavirin derivatives created in the virtual library are thenmade using conventional chemistry or can be obtained from a commercialsource.

The newly manufactured Ribavirin derivatives are then screened incharacterization assays, which determine the extent of adjuvant activityof the molecule and/or the extent of its ability to modulate of animmune response. Some characterization assays may involve virtual drugscreening software, such as C2.Ludi. C2.Ludi is a software program thatallows a user to explore databases of molecules (e.g., Ribavirinderivatives) for their ability to interact with the active site of aprotein of interest (e.g., RAC2 or another GTP binding protein). Basedupon predicted interactions discovered with the virtual drug screeningsoftware, the Ribavirin derivatives can be prioritized for furthercharacterization in conventional assays that determine adjuvant activityand/or the extent of a molecule to modulate an immune response.

Example 1 describes a characterization assay that was used to evaluatethe adjuvant activity of Ribavirin.

EXAMPLE 1

This characterization assay can be used with any Ribavirin derivative orcombinations of Ribavirin derivatives to determine the extent ofadjuvant activity of the particular vaccine formulation. Accordingly,groups of three to five Balb/c mice (BK Universal, Uppsala, Sweden) wereimmunized i.p or s.c. (e.g., at the base of the tail) with 10 μg or 100μg of recombinant hepatitis C virus non-structural 3 (NS3) protein. TherNS3 was dissolved in phosphate buffered saline (PBS) alone or PBScontaining 1 mg Ribavirin (obtained from ICN, Costa Mesa, Calif.). Micewere injected with a total volume of 100 μl per injection.

At two and four weeks following i.p. immunization, all mice were bled byretro-orbital sampling. Serum samples were collected and analyzed forthe presence of antibodies to rNS3. To determine the antibody titer, anenzyme immunoassay (EIA) was performed. (See e.g., Hultgren et al., JGen Virol. 79:2381-91 (1998) and Hultgren et al., Clin. Diagn. Lab.Immunol. 4:630-632 (1997), both of which are herein expresslyincorporated by reference in their entireties). The antibody levels wererecorded as the highest serum dilution giving an optical density at 405nm more than twice that of non-immunized mice.

Mice that received 10 μg or 100 μg rNS3 mixed with 1 mg Ribavirin in PBSdisplayed consistently higher levels of NS3 antibodies. The antibodytiter that was detected by EIA at two weeks post-immunization is shownin FIG. 1. The vaccine formulations having 1 mg of Ribavirin and either10 μg or 100 μg of rNS3 induced a significantly greater antibody titerthan the vaccine formulations composed of only rNS3. This data providesevidence that Ribavirin has an adjuvant effect on the humoral immuneresponse of an animal and thus, enhances the immune response to theantigen.

The example below describes experiments that were performed to determinethe amount of Ribavirin that was needed to elicit an adjuvant effect.

EXAMPLE 2

To determine the dose of Ribavirin that is required to provide anadjuvant effect, the following experiments were performed. Groups ofmice (three per group) were immunized with a 20 μg rNS3 alone or amixture of 20 μg rNS3 and 0.1 mg, 1 mg, or 10 mg Ribavirin. The levelsof antibody to the antigen were then determined by EIA. The meanendpoint titers at weeks 1 and 3 were plotted and are shown in FIG. 2.It was discovered that the adjuvant effect provided by Ribavirin haddifferent kinetics depending on the dose of Ribavirin provided. Forexample, low doses (<1 mg) of Ribavirin were found to enhance antibodylevels at week one but not at week three, whereas, higher doses (1-10mg) were found to enhance antibody levels at week three. These datafurther verify that Ribavirin can be administered as an adjuvant andestablish that that the dose of Ribavirin can modulate the kinetics ofthe adjuvant effect.

The example below describes another characterization assay that wasperformed to evaluate the ability of Ribavirin to modulate a cellularimmune response.

EXAMPLE 3

This characterization assay can be used with any Ribavirin derivative orcombinations of Ribavirin derivatives to determine the extent that aparticular vaccine formulation modulates a cellular immune response. Todetermine CD4⁺ T cell responses to Ribavirin-containing vaccine, groupsof mice were immunized s.c. with either 100 μg rNS3 in PBS or 100 μgrNS3 and 1 mg Ribavirin in PBS. The mice were sacrificed ten dayspost-immunization and their lymph nodes were harvested and drained. Invitro recall assays were then performed. (See e.g., Hultgren et al., JGen Virol. 79:2381-91 (1998) and Hultgren et al., Clin. Diagn. Lab.Immunol. 4:630-632 (1997), both of which are herein expresslyincorporated by reference in their entireties). The amount of CD4⁺ Tcell proliferation was determined at 96 h of culture by theincorporation of [³H] thymidine.

As shown in FIG. 2, mice that were immunized with 100 μg rNS3 mixed with1 mg Ribavirin had a much greater T cell proliferative response thanmice that were immunized with 100 μg rNS3 in PBS. This data providesevidence that Ribavirin can enhance a cellular immune response (e.g., bypromoting the effective priming of T cells).

The example below describes the use of Ribavirin in conjunction with acommercial vaccine preparation.

EXAMPLE 4

The adjuvant effect of Ribavirin was also tested when mixed with twodoses of a commercially available vaccine containing HBsAg and alum.(Engerix, SKB). Approximately 0.2 μg or 2 μg of Engerix vaccine wasmixed with either PBS or 1 mg Ribavirin in PBS and the mixtures wereinjected intra peritoneally into groups of mice (three per group). Abooster containing the same mixture was given on week four and all micewere bled on week six. The serum samples were diluted from 1:60 to1:37500 and the dilutions were tested by EIA, as described above, exceptthat purified human HBsAg (kindly provided by Professor DL Peterson,Commonwealth University, Va.) was used as the solid phase antigen. Asshown in TABLE 1, vaccine formulations having Ribavirin enhanced theresponse to 2 μg of an existing vaccine despite the fact that thevaccine already contained alum. That is, by adding Ribavirin to asuboptimal vaccine dose (i.e., one that does not induce detectableantibodies alone) antibodies became detectable, providing evidence thatthe addition of Ribavirin allows for the use of lower antigen amounts ina vaccine formulation without compromising the immune response.

TABLE 1 End point antibody titer to HBsAg in EIA 0.02 μg Engerix 0.2 μgEngerix No Ribavirin 1 mg Ribavirin No Ribavirin 1 mg Ribavirin Week #1#2 #3 #1 #2 #3 #1 #2 #3 #1 #2 #3 6 <60 <60 <60 <60 <60 <60 <60 <60 <60300 60 <60

Any antigen that can be used to generate an immune response in an animalcan be combined with Ribavirin so as to prepare the vaccines describedherein. That is, antigens that can be incorporated into such a vaccinecomprise bacterial antigens, fungal antigens, plant antigens, moldantigens, viral antigens, cancer cell antigens, toxin antigens, chemicalantigens, and self-antigens. Although many of these antigens aremolecules that induce a significant immune response without an adjuvant,Ribavirin can be administered in conjunction with or combined with“strong” or “weak” antigens to enhance the immune response. In addition,the use of Ribavirin as an adjuvant may allow for the use of loweramounts of vaccine antigens while retaining immunogenicity.

Preferred embodiments comprise Ribavirin and a viral antigen. Preferredviral antigens are hepatitis viral antigens. Vaccines can comprise, forexample, Ribavirin and an HBV antigen, HAV antigen, HCV antigen or anycombination of these antigens. Preferred viral antigens includehepatitis B surface antigen (HBsAg), hepatitis core antigen (HBcAg), andhepatitis E antigen (HBeAg).

For example, HCV vaccine embodiments comprise Ribavirin and a HCVpeptide of at least 3 consecutive amino acids of SEQ. ID. No.: 1. Thatis, a vaccine embodiment can have Ribavirin and a HCV peptide with alength of at least 3-10 consecutive amino acids, 10-50 consecutive aminoacids, 50-100 consecutive amino acids, 100-200 consecutive amino acids,200-400 consecutive amino acids, 400-800 consecutive amino acids,800-1200 consecutive amino acids, 1200-1600 consecutive amino acids,1600-2000 consecutive amino acids, 2000-2500 consecutive amino acids,and 2500-3011 consecutive amino acids of SEQ ID. No. 1. Preferred HCVvaccines comprise Ribavirin and a peptide of at least 3 consecutiveamino acids of HCV core protein (SEQ. ID. No. 2), HCV E1 protein (SEQ.ID. No. 3), HCV E2 protein (SEQ. ID. No. 4), HCV NS2 (SEQ. ID. No. 5),HCV NS3 (SEQ. ID. No. 6), HCV NS4A (SEQ. ID. No. 7), HCV NS4B (SEQ. ID.No. 8), or HCV NS5A/B (SEQ. ID. No. 9). That is, preferred HCV vaccinescan comprise Ribavirin and a peptide with a length of at least 3-10consecutive amino acids, 10-50 consecutive amino acids, 50-100consecutive amino acids, 100-200 consecutive amino acids, 200-400consecutive amino acids, 400-800 consecutive amino acids, and 800-1040consecutive amino acids of any one of (SEQ. ID. Nos. 2-9).

Similarly, preferred HBV vaccine embodiments comprise Ribavirin and aHBV peptide of at least 3 consecutive amino acids of HBsAg (SEQ. ID.No.: 10) or HBcAg and HBeAg (SEQ. ID. No. 11). That is, a vaccineembodiment can have Ribavirin and a HBV peptide with a length of atleast 3-10 consecutive amino acids, 10-50 consecutive amino acids,50-100 consecutive amino acids, 100-150 consecutive amino acids, 150-200consecutive amino acids, and 200-226 consecutive amino acids of eitherSEQ. ID. No. 10 or SEQ. ID. No. 11. Further, preferred HAV embodimentscomprise Ribavirin and a HAV peptide with a length of at least 3-10consecutive amino acids, 10-50 consecutive amino acids, 50-100consecutive amino acids, 100-200 consecutive amino acids, 200-400consecutive amino acids, 400-800 consecutive amino acids, 800-1200consecutive amino acids, 1200-1600 consecutive amino acids, 1600-2000consecutive amino acids, and 2000-2227 consecutive amino acids of SEQID. No. 12.

In addition to peptide antigens, nucleic acid-based antigens can be usedin the vaccine compositions described herein. Various nucleic acid-basedvaccines are known and it is contemplated that these compositions andapproaches to immunotherapy can be augmented by introducing Ribavirin(See e.g., U.S. Pat. No. 5,589,466, herein expressly incorporated byreference in its entirety).

By one approach, for example, a gene encoding a polypeptide antigen ofinterest is cloned into an expression vector capable of expressing thepolypeptide when introduced into a subject. The expression construct isintroduced into the subject in a mixture of Ribavirin or in conjunctionwith Ribavirin (e.g., Ribavirin is administered shortly after theexpression construct at the same site). Alternatively, RNA encoding apolypeptide antigen of interest is provided to the subject in a mixturewith Ribavirin or in conjunction with Ribavirin. Where thepolynucleotide is to be DNA, promoters suitable for use in variousvertebrate systems are well known. For example, for use in murinesystems, suitable strong promoters include RSV LTR, MPSV LTR, SV40 IEP,and metallothionein promoter. In humans, on the other hand, promoterssuch as CMV IEP can be used. All forms of DNA, whether replicating ornon-replicating, which do not become integrated into the genome, andwhich are expressible, can be used.

Preferred nucleic acid-based antigens include a nucleotide sequence ofat least 9 consecutive nucleotides of HCV (SEQ. ID. No. 13), HBV (SEQ.ID. No.: 14), or HAV (SEQ. ID. No. 15). That is, a nucleic acid basedantigen can comprise at least 9-25 consecutive nucleotides, 25-50consecutive nucleotides, 50-100 consecutive nucleotides, 100-200consecutive nucleotides, 200-500 consecutive nucleotides, 500-1000consecutive nucleotides, 1000-2000 consecutive nucleotides, 2000-4000consecutive nucleotides, 4000-8000 consecutive nucleotides, and8000-9416 consecutive nucleotides of any one of SEQ. ID. Nos.: 13-15 oran RNA that corresponds to these sequences.

The example below describes one approach for using a nucleic acid-basedantigen in conjunction with Ribavirin.

EXAMPLE 5

The following describes an approach to immunize an animal with a vaccinecomprising a nucleic acid-based antigen and Ribavirin. Five to six weekold female and male Balb/C mice are anesthetized by intraperitonealinjection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on theanterior thigh, and the quadriceps muscle is directly visualized. Onegroup of mice are injected with approximately 20 μg of an expressionconstruct having the gp-120 gene, driven by a cytomegalovirus (CMV)promotor and second group of mice are injected with approximately 5 μgof capped in vitro transcribed RNA (e.g., SP6, T7, or T3 (Ambion))encoding gp-120. These two groups are controls. A third group of mice isinjected with approximately 20 μg of the expression vector having thegp-120 gene and the CMV promoter mixed with 1 mg of Ribavirin and afourth group of mice is injected with approximately 5 μg of capped invitro transcribed RNA mixed with 1 mg Rbavirin. The vaccines areinjected in 0.1 ml of solution (PBS) in a 1 cc syringe through a 27gauge needle over one minute, approximately 0.5 cm from the distalinsertion site of the muscle into the knee and about 0.2 cm deep. Asuture is placed over the injection site for future localization, andthe skin is then closed with stainless steel clips.

Blood samples are obtained prior to the injection (Day 0) and up to morethan 40 days post injection. The serum from each sample is seriallydiluted and assayed in a standard ELISA technique assay for thedetection of antibody, using recombinant gp-120 protein made in yeast asthe antigen. Both IgG and IgM antibodies specific for gp-120 will bedetected in all samples, however, groups three and four, which containedthe Ribavirin, will exhibit a greater immune response to the gp-120 asmeasured by the amount and/or titer of antibody detected in the sera.

Many other ingredients can be present in the vaccine. For example, theRibavirin and antigen can be employed in admixture with conventionalexcipients (e.g., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral, enteral (e.g., oral) ortopical application that do not deleteriously react with the Ribavirinand/or antigen). Suitable pharmaceutically acceptable carriers include,but are not limited to, water, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, polyetylene glycols, gelatine,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy methylcellulose, polyvinyl pyrrolidone, etc. Many more suitablecarriers are described in Remmington's Pharmaceutical Sciences, 15thEdition, Easton:Mack Publishing Company, pages 1405-1412 and1461-1487(1975) and The National Formulary XIV, 14th Edition,Washington, American Pharmaceutical Association (1975), herein expresslyincorporated by reference in their entireties. Vaccines can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, coloring, flavoring and/oraromatic substances and the like that do not deleteriously react withRibavirin or the antigen.

The effective dose and method of administration of a particular vaccineformulation can vary based on the individual patient and the type andstage of the disease, as well as other factors known to those of skillin the art. Therapeutic efficacy and toxicity of the vaccines can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., ED50 (the dose therapeutically effective in50% of the population). The data obtained from cell culture assays andanimal studies can be used to formulate a range of dosage for human use.The dosage of the vaccines lies preferably within a range of circulatingconcentrations that include the ED50 with no toxicity. The dosage varieswithin this range depending upon the type of Ribavirin derivative andantigen, the dosage form employed, the sensitivity of the patient, andthe route of administration.

Since Ribavirin has been on the market for several years, many dosageforms and routes of administration are known. All known dosage forms androutes of administration can be provided within the context of theembodiments described herein. Preferably, an amount of Ribavirin that iseffective to enhance an immune response to an antigen in an animal canbe considered to be an amount that is sufficient to achieve a bloodserum level of antigen approximately 0.25-12.5 μg/ml in the animal,preferably, about 2.5 μg/ml. In some embodiments, the amount ofRibavirin is determined according to the body weight of the animal to begiven the vaccine. Accordingly, the amount of Ribavirin in a vaccineformulation can be from about 0.1-6.0 mg/kg body weight. That is, someembodiments have an amount of Ribavirin that corresponds toapproximately 0.1-1.0 mg/kg, 1.1-2.0 mg/kg, 2.1-3.0 mg/kg, 3.1-4.0mg/kg, 4.1-5.0 mg/kg, 5.1, and 6.0 mg/kg body weight of an animal. Moreconventionally, the vaccines contain approximately 0.25 mg-2000 mg ofRibavirin. That is, some embodiments have approximately 250 μg, 500 μg,1 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850mg, 900 mg, 1 g, 1.1 g, 1.2 g, 1.3 g, 1.4 g, 1.5 g, 1.6 g, 1.7 g, 1.8 g,1.9 g, and 2 g of Ribavirin.

Vaccines comprising various antigens and amounts of these antigens havebeen provided to animals for many years. Thus, conventional vaccinepreparations can be modified by adding an amount of Ribavirin that issufficient to enhance an immune response to the antigen. That is,existing conventional vaccine formulations can be modified by simplyadding Ribavirin to the preparation or by administering the conventionalvaccine in conjunction with Ribavirin (e.g., shortly before or afterproviding the antigen). As one of skill in the art will appreciate, theamount of antigens in a vaccine can vary depending on the type ofantigen and its immunogenicity. The amount of antigens in the vaccinescan vary accordingly. Nevertheless, as a general guide, the vaccines canhave approximately 0.25 mg-2000 mg of an antigen (e.g., a hepatitisviral antigen).

In some approaches described herein, the exact amount of Ribavirinand/or antigen is chosen by the individual physician in view of thepatient to be treated. Further, the amounts of Ribavirin can be added incombination to or separately from the same or equivalent amount ofantigen and these amounts can be adjusted during a particularvaccination protocol so as to provide sufficient levels in light ofpatient-specific or antigen-specific considerations. In this vein,patient-specific and antigen-specific factors that can be taken intoaccount include, but are not limited to, the severity of the diseasestate of the patient, age, and weight of the patient, diet, time andfrequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy.

Routes of administration of the vaccines described herein include, butare not limited to, transdermal, parenteral, gastrointestinal,transbronchial, and transalveolar. Transdermal administration can beaccomplished by application of a cream, rinse, gel, etc. capable ofallowing Ribavirin and antigen to penetrate the skin. Parenteral routesof administration include, but are not limited to, electrical or directinjection such as direct injection into a central venous line,intravenous, intramuscular, intraperitoneal, intradermal, orsubcutaneous injection. Gastrointestinal routes of administrationinclude, but are not limited to, ingestion and rectal. Transbronchialand transalveolar routes of administration include, but are not limitedto, inhalation, either via the mouth or intranasally.

Compositions having Ribavirin and an antigen that are suitable fortransdermal administration include, but are not limited to,pharmaceutically acceptable suspensions, oils, creams, and ointmentsapplied directly to the skin or incorporated into a protective carriersuch as a transdermal device (“transdermal patch”). Examples of suitablecreams, ointments, etc. can be found, for instance, in the Physician'sDesk Reference. Examples of suitable transdermal devices are described,for instance, in U.S. Pat. No. 4,818,540 issued Apr. 4, 1989 to Chinen,et al., herein expressly incorporated by reference in its entirety.

Compositions having Ribavirin and an antigen that are suitable forparenteral administration include, but are not limited to,pharmaceutically acceptable sterile isotonic solutions. Such solutionsinclude, but are not limited to, saline, phosphate buffered saline andoil preparations for injection into a central venous line, intravenous,intramuscular, intraperitoneal, intradermal, or subcutaneous injection.

Compositions having Ribavirin and an antigen that are suitable fortransbronchial and transalveolar administration include, but not limitedto, various types of aerosols for inhalation. Devices suitable fortransbronchial and transalveolar administration of these are alsoembodiments. Such devices include, but are not limited to, atomizers andvaporizers. Many forms of currently available atomizers and vaporizerscan be readily adapted to deliver vaccines having Ribavirin and anantigen.

Compositions having Ribavirin and an antigen that are suitable forgastrointestinal administration include, but not limited to,pharmaceutically acceptable powders, pills or liquids for ingestion andsuppositories for rectal administration.

Once the vaccine comprising Ribavirin and an antigen has been obtained,it can be administered to a subject in need to treat or preventdiseases. The next section describes methods that employ the vaccinesdescribed above.

Methods of use of Vaccines that Contain Ribavirin

The vaccines containing Ribavirin and an antigen can be used to treatand prevent a vast spectrum of diseases and can enhance the immuneresponse of an animal to an antigen. As one of skill in the art willappreciate conventional vaccines have been administered to subjects inneed of treatment or prevention of bacterial diseases, viral diseases,fungal diseases, and cancer. Because the vaccines described hereininclude conventional vaccines, which have been modified by the additionof Ribavirin, the methods described herein include the treatment andprevention of a disease using a vaccine that comprises an antigen andRibavirin.

Preferred embodiments concern methods of treating or preventinghepatitis infection. In these embodiments, an animal in need is provideda hepatitis antigen (e.g., a peptide antigen or nucleic acid-basedantigen) and an amount of Ribavirin sufficient to exhibit an adjuvantactivity in said animal. Accordingly, an animal can be identified as onein need by using currently available diagnostic testing or clinicalevaluation. The range of hepatitis viral antigens that can be used withthese embodiments is diverse. Preferred hepatitis viral antigens includean HBV antigen, an HAV antigen, an HCV antigen, nucleic acids encodingthese antigens, or any combination thereof. Highly preferred embodimentsinclude an HBV antigen selected from the group consisting of hepatitis Bsurface antigen (HBsAg), hepatitis core antigen (HBcAg), and hepatitis Eantigen (HBeAg), in particular, the peptide and nucleic acid-basedantigens describes supra. The Ribavirin and antigen can be providedseparately or in combination, and other adjuvants (e.g., oil, alum, orother agents that enhance an immune response) can also be provided tothe animal in need. Thus, preferred embodiments include methods oftreating or preventing hepatitis in an animal (e.g., HBV) by identifyingan infected animal or an animal at risk of infection and providing saidanimal a hepatitis antigen (e.g., HBsAg, HBcAg, and HBeAg) and an amountof Ribavirin sufficient to exhibit adjuvant activity.

Other embodiments include methods of enhancing an immune response to anantigen by providing an animal in need with an amount of Ribavirin thatis effective to enhance said immune response. In these embodiments, ananimal in need of an enhanced immune response to an antigen isidentified by using currently available diagnostic testing or clinicalevaluation. Oftentimes these individuals will be suffering from adisease (e.g., bacterial, fungal, mold, viral, or cancer) or are at riskfrom contracting the disease. However, an animal in need of an enhancedimmune response can be an animal that has been poisoned (e.g., bit by apoisonous insect or animal) or that has been exposed to a toxin or othertoxic compound. Once identified, these animals are provided anappropriate antigen and an amount of Ribavirin effective to enhance animmune response in the animal.

As above, the hepatitis viral antigens that can be used with theseembodiments include, but are not limited to, an HBV antigen, an HAVantigen, an HCV antigen, a nucleic acid encoding these molecules, or anycombination thereof. Highly preferred embodiments include an HBV antigenselected from the group consisting of hepatitis B surface antigen(HBsAg), hepatitis core antigen (HBcAg), and hepatitis E antigen(HBeAg), in particular, the peptide and nucleic acid-based antigensdescribed supra. The Ribavirin and antigen can be provided separately orin combination, and other adjuvants (e.g., oil, alum, or other agentsthat enhance an immune response) can also be provided to the animal inneed. Thus, preferred embodiments include methods of enhancing an immuneresponse to a hepatitis antigen (e.g., HBV) by identifying an animal inneed and providing the animal a hepatitis antigen (e.g., HBsAg, HBcAg,and HBeAg) and an amount of Ribavirin that is effective to enhance animmune response in the animal.

Although the invention has been described with reference to embodimentsand examples, it should be understood that various modifications can bemade without departing from the spirit of the invention. Accordingly,the invention is limited only by the following claims. All referencescited herein are hereby expressly incorporated by reference.

                   #             SEQUENCE LISTING<160> NUMBER OF SEQ ID NOS: 15 <210> SEQ ID NO 1 <211> LENGTH: 3011<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus sequenc #e <400> SEQUENCE: 1Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Th #r Lys Arg Asn Thr Asn 1               5   #                10   #                15Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gl #y Gly Gln Ile Val Gly            20       #            25       #            30Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Ar #g Leu Gly Val Arg Ala        35           #        40           #        45Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Ar #g Gly Arg Arg Gln Pro    50               #    55               #    60Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Th #r Trp Ala Gln Pro Gly65                   #70                   #75                   #80Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cy #s Gly Trp Ala Gly Trp                85   #                90   #                95Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Tr #p Gly Pro Thr Asp Pro            100       #           105       #           110Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Il #e Asp Thr Leu Thr Cys        115           #       120           #       125Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Le #u Val Gly Ala Pro Leu    130               #   135               #   140Gly Gly Ala Ala Arg Ala Leu Ala His Gly Va #l Arg Val Leu Glu Asp145                 1 #50                 1 #55                 1 #60Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gl #y Cys Ser Phe Ser Ile                165   #               170   #               175Phe Leu Leu Ala Leu Leu Ser Cys Leu Thr Va #l Pro Ala Ser Ala Tyr            180       #           185       #           190Gln Val Arg Asn Ser Ser Gly Leu Tyr His Va #l Thr Asn Asp Cys Pro        195           #       200           #       205Asn Ser Ser Val Val Tyr Glu Ala Ala Asp Al #a Ile Leu His Thr Pro    210               #   215               #   220Gly Cys Val Pro Cys Val Arg Glu Gly Asn Al #a Ser Arg Cys Trp Val225                 2 #30                 2 #35                 2 #40Ala Val Thr Pro Thr Val Ala Thr Arg Asp Gl #y Lys Leu Pro Thr Thr                245   #               250   #               255Gln Leu Arg Arg His Ile Asp Leu Leu Val Gl #y Ser Ala Thr Leu Cys            260       #           265       #           270Ser Ala Leu Tyr Val Gly Asp Leu Cys Gly Se #r Val Phe Leu Val Gly        275           #       280           #       285Gln Leu Phe Thr Phe Ser Pro Arg His His Tr #p Thr Thr Gln Asp Cys    290               #   295               #   300Asn Cys Ser Ile Tyr Pro Gly His Ile Thr Gl #y His Arg Met Ala Trp305                 3 #10                 3 #15                 3 #20Asn Met Met Met Asn Trp Ser Pro Thr Ala Al #a Leu Val Val Ala Gln                325   #               330   #               335Leu Leu Arg Ile Pro Gln Ala Ile Met Asp Me #t Ile Ala Gly Ala His            340       #           345       #           350Trp Gly Val Leu Ala Gly Ile Lys Tyr Phe Se #r Met Val Gly Asn Trp        355           #       360           #       365Ala Lys Val Leu Val Val Leu Leu Leu Phe Al #a Gly Val Asp Ala Glu    370               #   375               #   380Thr His Val Thr Gly Gly Asn Ala Gly Arg Th #r Thr Ala Gly Leu Val385                 3 #90                 3 #95                 4 #00Gly Leu Leu Thr Pro Gly Ala Lys Gln Asn Il #e Gln Leu Ile Asn Thr                405   #               410   #               415Asn Gly Ser Trp His Ile Asn Ser Thr Ala Le #u Asn Cys Asn Glu Ser            420       #           425       #           430Leu Asn Thr Gly Trp Leu Ala Gly Leu Phe Ty #r Gln His Lys Phe Asn        435           #       440           #       445Ser Ser Gly Cys Pro Glu Arg Leu Ala Ser Cy #s Arg Arg Leu Thr Asp    450               #   455               #   460Phe Ala Gln Gly Trp Gly Pro Ile Ser Tyr Al #a Asn Gly Ser Gly Leu465                 4 #70                 4 #75                 4 #80Asp Glu Arg Pro Tyr Cys Trp His Tyr Pro Pr #o Arg Pro Cys Gly Ile                485   #               490   #               495Val Pro Ala Lys Ser Val Cys Gly Pro Val Ty #r Cys Phe Thr Pro Ser            500       #           505       #           510Pro Val Val Val Gly Thr Thr Asp Arg Ser Gl #y Ala Pro Thr Tyr Ser        515           #       520           #       525Trp Gly Ala Asn Asp Thr Asp Val Phe Val Le #u Asn Asn Thr Arg Pro    530               #   535               #   540Pro Leu Gly Asn Trp Phe Gly Cys Thr Trp Me #t Asn Ser Thr Gly Phe545                 5 #50                 5 #55                 5 #60Thr Lys Val Cys Gly Ala Pro Pro Cys Val Il #e Gly Gly Val Gly Asn                565   #               570   #               575Asn Thr Leu Leu Cys Pro Thr Asp Cys Phe Ar #g Lys Tyr Pro Glu Ala            580       #           585       #           590Thr Tyr Ser Arg Cys Gly Ser Gly Pro Arg Il #e Thr Pro Arg Cys Met        595           #       600           #       605Val Asp Tyr Pro Tyr Arg Leu Trp His Tyr Pr #o Cys Thr Ile Asn Tyr    610               #   615               #   620Thr Ile Phe Lys Val Arg Met Tyr Val Gly Gl #y Val Glu His Arg Leu625                 6 #30                 6 #35                 6 #40Glu Ala Ala Cys Asn Trp Thr Arg Gly Glu Ar #g Cys Asp Leu Glu Asp                645   #               650   #               655Arg Asp Arg Ser Glu Leu Ser Pro Leu Leu Le #u Ser Thr Thr Gln Trp            660       #           665       #           670Gln Val Leu Pro Cys Ser Phe Thr Thr Leu Pr #o Ala Leu Ser Thr Gly        675           #       680           #       685Leu Ile His Leu His Gln Asn Ile Val Asp Va #l Gln Tyr Leu Tyr Gly    690               #   695               #   700Val Gly Ser Ser Ile Ala Ser Trp Ala Ile Ly #s Trp Glu Tyr Val Val705                 7 #10                 7 #15                 7 #20Leu Leu Phe Leu Leu Leu Ala Asp Ala Arg Va #l Cys Ser Cys Leu Trp                725   #               730   #               735Met Met Leu Leu Ile Ser Gln Ala Glu Ala Al #a Leu Glu Asn Leu Val            740       #           745       #           750Ile Leu Asn Ala Ala Ser Leu Ala Gly Thr Hi #s Gly Leu Val Ser Phe        755           #       760           #       765Leu Val Phe Phe Cys Phe Ala Trp Tyr Leu Ly #s Gly Arg Trp Val Pro    770               #   775               #   780Gly Ala Val Tyr Ala Leu Tyr Gly Met Trp Pr #o Leu Leu Leu Leu Leu785                 7 #90                 7 #95                 8 #00Leu Ala Leu Pro Gln Arg Ala Tyr Ala Leu As #p Thr Glu Val Ala Ala                805   #               810   #               815Ser Cys Gly Gly Val Val Leu Val Gly Leu Me #t Ala Leu Thr Leu Ser            820       #           825       #           830Pro Tyr Tyr Lys Arg Tyr Ile Ser Trp Cys Me #t Trp Trp Leu Gln Tyr        835           #       840           #       845Phe Leu Thr Arg Val Glu Ala Gln Leu His Va #l Trp Val Pro Pro Leu    850               #   855               #   860Asn Val Arg Gly Gly Arg Asp Ala Val Ile Le #u Leu Thr Cys Val Val865                 8 #70                 8 #75                 8 #80His Pro Ala Leu Val Phe Asp Ile Thr Lys Le #u Leu Leu Ala Ile Phe                885   #               890   #               895Gly Pro Leu Trp Ile Leu Gln Ala Ser Leu Le #u Lys Val Pro Tyr Phe            900       #           905       #           910Val Arg Val Gln Gly Leu Leu Arg Ile Cys Al #a Leu Ala Arg Lys Ile        915           #       920           #       925Ala Gly Gly His Tyr Val Gln Met Ala Ile Il #e Lys Leu Gly Ala Leu    930               #   935               #   940Thr Gly Thr Cys Val Tyr Asn His Leu Ala Pr #o Leu Arg Asp Trp Ala945                 9 #50                 9 #55                 9 #60His Asn Gly Leu Arg Asp Leu Ala Val Ala Va #l Glu Pro Val Val Phe                965   #               970   #               975Ser Arg Met Glu Thr Lys Leu Ile Thr Trp Gl #y Ala Asp Thr Ala Ala            980       #           985       #           990Cys Gly Asp Ile Ile Asn Gly Leu Pro Val Se #r Ala Arg Arg Gly Gln        995           #       1000           #      1005Glu Ile Leu Leu Gly Pro Ala Asp Gly Met Va #l Ser Lys Gly Trp Arg    1010              #   1015               #  1020Leu Leu Ala Pro Ile Thr Ala Tyr Ala Gln Gl #n Thr Arg Gly Leu Leu1025                1030 #                1035  #               1040Gly Cys Ile Ile Thr Ser Leu Thr Gly Arg As #p Lys Asn Gln Val Glu                1045  #               1050   #              1055Gly Glu Val Gln Ile Val Ser Thr Ala Thr Gl #n Thr Phe Leu Ala Thr            1060      #           1065       #          1070Cys Ile Asn Gly Val Cys Trp Thr Val Tyr Hi #s Gly Ala Gly Thr Arg        1075          #       1080           #      1085Thr Ile Ala Ser Pro Lys Gly Pro Val Ile Gl #n Thr Tyr Thr Asn Val    1090              #   1095               #  1100Asp Gln Asp Leu Val Gly Trp Pro Ala Pro Gl #n Gly Ser Arg Ser Leu1105                1110 #                1115  #               1120Thr Pro Cys Thr Cys Gly Ser Ser Asp Leu Ty #r Leu Val Thr Arg His                1125  #               1130   #              1135Ala Asp Val Ile Pro Val Arg Arg Arg Gly As #p Ser Arg Gly Ser Leu            1140      #           1145       #          1150Leu Ser Pro Arg Pro Ile Ser Tyr Leu Lys Gl #y Ser Ser Gly Gly Pro        1155          #       1160           #      1165Leu Leu Cys Pro Thr Gly His Ala Val Gly Le #u Phe Arg Ala Ala Val    1170              #   1175               #  1180Cys Thr Arg Gly Val Ala Lys Ala Val Asp Ph #e Ile Pro Val Glu Asn1185                1190 #                1195  #               1200Leu Glu Thr Thr Met Arg Ser Pro Val Phe Th #r Asp Asn Ser Ser Pro                1205  #               1210   #              1215Pro Ala Val Pro Gln Ser Phe Gln Val Ala Hi #s Leu His Ala Pro Thr            1220      #           1225       #          1230Gly Ser Gly Lys Ser Thr Lys Val Pro Ala Al #a Tyr Ala Ala Lys Gly        1235          #       1240           #      1245Tyr Lys Val Leu Val Leu Asn Pro Ser Val Al #a Ala Thr Leu Gly Phe    1250              #   1255               #  1260Gly Ala Tyr Met Ser Lys Ala His Gly Val As #p Pro Asn Ile Arg Thr1265                1270 #                1275  #               1280Gly Val Arg Thr Ile Thr Thr Gly Ser Pro Il #e Thr Tyr Ser Thr Tyr                1285  #               1290   #              1295Gly Lys Phe Leu Ala Asp Ala Gly Cys Ser Gl #y Gly Ala Tyr Asp Ile            1300      #           1305       #          1310Ile Ile Cys Asp Glu Cys His Ser Thr Asp Al #a Thr Ser Ile Ser Gly        1315          #       1320           #      1325Ile Gly Thr Val Leu Asp Gln Ala Glu Thr Al #a Gly Ala Arg Leu Val    1330              #   1335               #  1340Val Leu Ala Thr Ala Thr Pro Pro Gly Ser Va #l Thr Val Ser His Pro1345                1350 #                1355  #               1360Asn Ile Glu Glu Val Ala Leu Ser Thr Thr Gl #y Glu Ile Pro Phe Tyr                1365  #               1370   #              1375Gly Lys Ala Ile Pro Leu Glu Val Ile Lys Gl #y Gly Arg His Leu Ile            1380      #           1385       #          1390Phe Cys His Ser Lys Lys Lys Cys Asp Glu Le #u Ala Ala Lys Leu Val        1395          #       1400           #      1405Ala Leu Gly Ile Asn Ala Val Ala Tyr Tyr Ar #g Gly Leu Asp Val Ser    1410              #   1415               #  1420Val Ile Pro Thr Ser Gly Asp Val Val Val Va #l Ser Thr Asp Ala Leu1425                1430 #                1435  #               1440Met Thr Gly Phe Thr Gly Asp Phe Asp Ser Va #l Ile Asp Cys Asn Thr                1445  #               1450   #              1455Cys Val Thr Gln Thr Val Asp Phe Ser Leu As #p Pro Thr Phe Thr Ile            1460      #           1465       #          1470Glu Thr Thr Thr Leu Pro Gln Asp Ala Val Se #r Arg Thr Gln Arg Arg        1475          #       1480           #      1485Gly Arg Thr Gly Arg Gly Lys Pro Gly Ile Ty #r Arg Phe Val Ala Pro    1490              #   1495               #  1500Gly Glu Arg Pro Ser Gly Met Phe Asp Ser Se #r Val Leu Cys Glu Cys1505                1510 #                1515  #               1520Tyr Asp Ala Gly Cys Ala Trp Tyr Glu Leu Th #r Pro Ala Glu Thr Thr                1525  #               1530   #              1535Val Arg Leu Arg Ala Tyr Met Asn Thr Pro Gl #y Leu Pro Val Cys Gln            1540      #           1545       #          1550Asp His Leu Gly Phe Trp Glu Gly Val Phe Th #r Gly Leu Thr His Ile        1555          #       1560           #      1565Asp Ala His Phe Leu Ser Gln Thr Lys Gln Se #r Gly Glu Asn Phe Pro    1570              #   1575               #  1580Tyr Leu Val Ala Tyr Gln Ala Thr Val Cys Al #a Arg Ala Gln Ala Pro1585                1590 #                1595  #               1600Pro Pro Ser Trp Asp Gln Met Arg Lys Cys Le #u Ile Arg Leu Lys Pro                1605  #               1610   #              1615Thr Leu His Gly Pro Thr Pro Leu Leu Tyr Ar #g Leu Gly Ala Val Gln            1620      #           1625       #          1630Asn Glu Val Thr Leu Thr His Pro Ile Thr Ly #s Tyr Ile Met Thr Cys        1635          #       1640           #      1645Met Ser Ala Asp Leu Glu Val Val Thr Ser Th #r Trp Val Leu Val Gly    1650              #   1655               #  1660Gly Val Leu Ala Ala Leu Ala Ala Tyr Cys Le #u Ser Thr Gly Cys Val1665                1670 #                1675  #               1680Val Ile Val Gly Arg Ile Val Leu Ser Gly Ly #s Pro Ala Ile Ile Pro                1685  #               1690   #              1695Asp Arg Glu Val Leu Tyr Gln Glu Phe Asp Gl #u Met Glu Glu Cys Ser            1700      #           1705       #          1710Gln His Leu Pro Tyr Ile Glu Gln Gly Met Me #t Leu Ala Glu Gln Phe        1715          #       1720           #      1725Lys Gln Lys Ala Leu Gly Leu Leu Gln Thr Al #a Ser Arg His Ala Glu    1730              #   1735               #  1740Val Ile Thr Pro Ala Val Gln Thr Asn Trp Gl #n Lys Leu Glu Val Phe1745                1750 #                1755  #               1760Trp Ala Lys His Met Trp Asn Phe Ile Ser Gl #y Ile Gln Tyr Leu Ala                1765  #               1770   #              1775Gly Leu Ser Thr Leu Pro Gly Asn Pro Ala Il #e Ala Ser Leu Met Ala            1780      #           1785       #          1790Phe Thr Ala Ala Val Thr Ser Pro Leu Thr Th #r Gly Gln Thr Leu Leu        1795          #       1800           #      1805Phe Asn Ile Leu Gly Gly Trp Val Ala Ala Gl #n Leu Ala Ala Pro Gly    1810              #   1815               #  1820Ala Ala Thr Ala Phe Val Gly Ala Gly Leu Al #a Gly Ala Ala Leu Asp1825                1830 #                1835  #               1840Ser Val Gly Leu Gly Lys Val Leu Val Asp Il #e Leu Ala Gly Tyr Gly                1845  #               1850   #              1855Ala Gly Val Ala Gly Ala Leu Val Ala Phe Ly #s Ile Met Ser Gly Glu            1860      #           1865       #          1870Val Pro Ser Thr Glu Asp Leu Val Asn Leu Le #u Pro Ala Ile Leu Ser        1875          #       1880           #      1885Pro Gly Ala Leu Ala Val Gly Val Val Phe Al #a Ser Ile Leu Arg Arg    1890              #   1895               #  1900Arg Val Gly Pro Gly Glu Gly Ala Val Gln Tr #p Met Asn Arg Leu Ile1905                1910 #                1915  #               1920Ala Phe Ala Ser Arg Gly Asn His Val Ser Pr #o Thr His Tyr Val Pro                1925  #               1930   #              1935Glu Ser Asp Ala Ala Ala Arg Val Thr Ala Il #e Leu Ser Ser Leu Thr            1940      #           1945       #          1950Val Thr Gln Leu Leu Arg Arg Leu His Gln Tr #p Ile Ser Ser Glu Cys        1955          #       1960           #      1965Thr Thr Pro Cys Ser Gly Ser Trp Leu Arg As #p Ile Trp Asp Trp Ile    1970              #   1975               #  1980Cys Glu Val Leu Ser Asp Phe Lys Thr Trp Le #u Lys Ala Lys Leu Met1985                1990 #                1995  #               2000Pro Gln Leu Pro Gly Ile Pro Phe Val Ser Cy #s Gln Arg Gly Tyr Arg                2005  #               2010   #              2015Gly Val Trp Arg Gly Asp Gly Ile Met His Th #r Arg Cys His Cys Gly            2020      #           2025       #          2030Ala Glu Ile Thr Gly His Val Lys Asn Gly Th #r Met Arg Ile Val Gly        2035          #       2040           #      2045Pro Arg Thr Cys Lys Asn Met Trp Ser Gly Th #r Phe Phe Ile Asn Ala    2050              #   2055               #  2060Tyr Thr Thr Gly Pro Cys Thr Pro Leu Pro Al #a Pro Asn Tyr Lys Phe2065                2070 #                2075  #               2080Ala Leu Trp Arg Val Ser Ala Glu Glu Tyr Va #l Glu Ile Arg Arg Val                2085  #               2090   #              2095Gly Asp Phe His Tyr Val Ser Gly Met Thr Th #r Asp Asn Leu Lys Cys            2100      #           2105       #          2110Pro Cys Gln Ile Pro Ser Pro Glu Phe Phe Th #r Glu Leu Asp Gly Val        2115          #       2120           #      2125Arg Leu His Arg Phe Ala Pro Pro Cys Lys Pr #o Leu Leu Arg Glu Glu    2130              #   2135               #  2140Val Ser Phe Arg Val Gly Leu His Glu Tyr Pr #o Val Gly Ser Gln Leu2145                2150 #                2155  #               2160Pro Cys Glu Pro Glu Pro Asp Val Ala Val Le #u Thr Ser Met Leu Thr                2165  #               2170   #              2175Asp Pro Ser His Ile Thr Ala Glu Ala Ala Gl #y Arg Arg Leu Ala Arg            2180      #           2185       #          2190Gly Ser Pro Pro Ser Met Ala Ser Ser Ser Al #a Ser Gln Leu Ser Ala        2195          #       2200           #      2205Pro Ser Leu Lys Ala Thr Cys Thr Ala Asn Hi #s Asp Ser Pro Asp Ala    2210              #   2215               #  2220Glu Leu Ile Glu Ala Asn Leu Leu Trp Arg Gl #n Glu Met Gly Gly Asn2225                2230 #                2235  #               2240Ile Thr Arg Val Glu Ser Glu Asn Lys Val Va #l Ile Leu Asp Ser Phe                2245  #               2250   #              2255Asp Pro Leu Val Ala Glu Glu Asp Glu Arg Gl #u Val Ser Val Pro Ala            2260      #           2265       #          2270Glu Ile Leu Arg Lys Ser Arg Arg Phe Ala Pr #o Ala Leu Pro Val Trp        2275          #       2280           #      2285Ala Arg Pro Asp Tyr Asn Pro Leu Leu Val Gl #u Thr Trp Lys Lys Pro    2290              #   2295               #  2300Asp Tyr Glu Pro Pro Val Val His Gly Cys Pr #o Leu Pro Pro Pro Arg2305                2310 #                2315  #               2320Ser Pro Pro Val Pro Pro Pro Arg Lys Lys Ar #g Thr Val Val Leu Thr                2325  #               2330   #              2335Glu Ser Thr Leu Pro Thr Ala Leu Ala Glu Le #u Ala Thr Lys Ser Phe            2340      #           2345       #          2350Gly Ser Ser Ser Thr Ser Gly Ile Thr Gly As #p Asn Thr Thr Thr Ser        2355          #       2360           #      2365Ser Glu Pro Ala Pro Ser Gly Cys Pro Pro As #p Ser Asp Val Glu Ser    2370              #   2375               #  2380Tyr Ser Ser Met Pro Pro Leu Glu Gly Glu Pr #o Gly Asp Pro Asp Leu2385                2390 #                2395  #               2400Ser Asp Gly Ser Trp Ser Thr Val Ser Ser Gl #y Ala Asp Thr Glu Asp                2405  #               2410   #              2415Val Val Cys Cys Ser Met Ser Tyr Ser Trp Th #r Gly Ala Leu Val Thr            2420      #           2425       #          2430Pro Cys Ala Ala Glu Glu Gln Lys Leu Pro Il #e Asn Ala Leu Ser Asn        2435          #       2440           #      2445Ser Leu Leu Arg His His Asn Leu Val Tyr Se #r Thr Thr Ser Arg Ser    2450              #   2455               #  2460Ala Cys Gln Arg Lys Lys Lys Val Thr Phe As #p Arg Leu Gln Val Leu2465                2470 #                2475  #               2480Asp Ser His Tyr Gln Asp Val Leu Lys Glu Va #l Lys Ala Ala Ala Ser                2485  #               2490   #              2495Lys Val Lys Ala Asn Leu Leu Ser Val Glu Gl #u Ala Cys Ser Leu Ala            2500      #           2505       #          2510Pro Pro His Ser Ala Lys Ser Lys Phe Gly Ty #r Gly Ala Lys Asp Val        2515          #       2520           #      2525Arg Cys His Ala Arg Lys Ala Val Ala His Il #e Asn Ser Val Trp Lys    2530              #   2535               #  2540Asp Leu Leu Glu Asp Ser Val Thr Pro Ile As #p Thr Thr Ile Met Ala2545                2550 #                2555  #               2560Lys Asn Glu Val Phe Cys Val Gln Pro Glu Ly #s Gly Gly Arg Lys Pro                2565  #               2570   #              2575Ala Arg Leu Ile Val Phe Pro Asp Leu Gly Va #l Arg Val Cys Glu Lys            2580      #           2585       #          2590Met Ala Leu Tyr Asp Val Val Ser Lys Leu Pr #o Leu Ala Val Met Gly        2595          #       2600           #      2605Ser Ser Tyr Gly Phe Gln Tyr Ser Pro Gly Gl #n Arg Val Glu Phe Leu    2610              #   2615               #  2620Val Gln Ala Trp Lys Ser Lys Lys Thr Pro Me #t Gly Leu Ser Tyr Asp2625                2630 #                2635  #               2640Thr Arg Cys Phe Asp Ser Thr Val Thr Glu Se #r Asp Ile Arg Thr Glu                2645  #               2650   #              2655Glu Ala Ile Tyr Gln Cys Cys Asp Leu Asp Pr #o Gln Ala Arg Val Ala            2660      #           2665       #          2670Ile Lys Ser Leu Thr Glu Arg Leu Tyr Val Gl #y Gly Pro Leu Thr Asn        2675          #       2680           #      2685Ser Arg Gly Glu Asn Cys Gly Tyr Arg Arg Cy #s Arg Ala Ser Arg Val    2690              #   2695               #  2700Leu Thr Thr Ser Cys Gly Asn Thr Leu Thr Ar #g Tyr Ile Lys Ala Arg2705                2710 #                2715  #               2720Ala Ala Cys Arg Ala Ala Gly Leu Gln Asp Cy #s Thr Met Leu Val Cys                2725  #               2730   #              2735Gly Asp Asp Leu Val Val Ile Cys Glu Ser Al #a Gly Val Gln Glu Asp            2740      #           2745       #          2750Ala Ala Ser Leu Arg Ala Phe Thr Glu Ala Me #t Thr Arg Tyr Ser Ala        2755          #       2760           #      2765Pro Pro Gly Asp Pro Pro Gln Pro Glu Tyr As #p Leu Glu Leu Ile Thr    2770              #   2775               #  2780Ser Cys Ser Ser Asn Val Ser Val Ala His As #p Gly Ala Gly Lys Arg2785                2790 #                2795  #               2800Val Tyr Tyr Leu Thr Arg Asp Pro Thr Thr Pr #o Leu Ala Arg Ala Ala                2805  #               2810   #              2815Trp Glu Thr Ala Arg His Thr Pro Val Asn Se #r Trp Leu Gly Asn Ile            2820      #           2825       #          2830Ile Met Phe Ala Pro Thr Leu Trp Ala Arg Me #t Ile Leu Met Thr His        2835          #       2840           #      2845Phe Phe Ser Val Leu Ile Ala Arg Asp Gln Le #u Glu Gln Ala Leu Asn    2850              #   2855               #  2860Cys Glu Ile Tyr Gly Ala Cys Tyr Ser Ile Gl #u Pro Leu Asp Leu Pro2865                2870 #                2875  #               2880Pro Ile Ile Gln Arg Leu His Gly Leu Ser Al #a Phe Ser Leu His Ser                2885  #               2890   #              2895Tyr Ser Pro Gly Glu Ile Asn Arg Val Ala Al #a Cys Leu Arg Lys Leu            2900      #           2905       #          2910Gly Val Pro Pro Leu Arg Ala Trp Arg His Ar #g Ala Trp Ser Val Arg        2915          #       2920           #      2925Ala Arg Leu Leu Ala Arg Gly Gly Lys Ala Al #a Ile Cys Gly Lys Tyr    2930              #   2935               #  2940Leu Phe Asn Trp Ala Val Arg Thr Lys Leu Ly #s Leu Thr Pro Ile Thr2945                2950 #                2955  #               2960Ala Ala Gly Arg Leu Asp Leu Ser Gly Trp Ph #e Thr Ala Gly Tyr Ser                2965  #               2970   #              2975Gly Gly Asp Ile Tyr His Ser Val Ser His Al #a Arg Pro Arg Trp Phe            2980      #           2985       #          2990Trp Phe Cys Leu Leu Leu Leu Ala Ala Gly Va #l Gly Ile Tyr Leu Leu        2995          #       3000           #      3005 Pro Asn Arg    3010 <210> SEQ ID NO 2 <211> LENGTH: 182 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus core  #protein sequence<400> SEQUENCE: 2 Met Ser Thr Asn Pro Lys Pro Gln Arg Lys Th#r Lys Arg Asn Thr Asn  1               5   #                10  #                15 Arg Arg Pro Gln Asp Val Lys Phe Pro Gly Gl#y Gly Gln Ile Val Gly             20       #            25      #            30 Gly Val Tyr Leu Leu Pro Arg Arg Gly Pro Ar#g Leu Gly Val Arg Ala         35           #        40          #        45 Thr Arg Lys Thr Ser Glu Arg Ser Gln Pro Ar#g Gly Arg Arg Gln Pro     50               #    55              #    60 Ile Pro Lys Ala Arg Arg Pro Glu Gly Arg Th#r Trp Ala Gln Pro Gly 65                   #70                  #75                   #80 Tyr Pro Trp Pro Leu Tyr Gly Asn Glu Gly Cy#s Gly Trp Ala Gly Trp                 85   #                90  #                95 Leu Leu Ser Pro Arg Gly Ser Arg Pro Ser Tr#p Gly Pro Thr Asp Pro             100       #           105      #           110 Arg Arg Arg Ser Arg Asn Leu Gly Lys Val Il#e Asp Thr Leu Thr Cys         115           #       120          #       125 Gly Phe Ala Asp Leu Met Gly Tyr Ile Pro Le#u Val Gly Ala Pro Leu     130               #   135              #   140 Gly Gly Ala Ala Arg Ala Leu Ala His Gly Va#l Arg Val Leu Glu Asp 145                 1 #50                 1#55                 1 #60 Gly Val Asn Tyr Ala Thr Gly Asn Leu Pro Gl#y Cys Ser Phe Ser Ile                 165   #               170  #               175 Phe Leu Leu Ala Leu Leu             180<210> SEQ ID NO 3 <211> LENGTH: 197 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus E1 p #rotein sequence<400> SEQUENCE: 3 Ser Cys Leu Thr Val Pro Ala Ser Ala Tyr Gl#n Val Arg Asn Ser Ser  1               5   #                10  #                15 Gly Leu Tyr His Val Thr Asn Asp Cys Pro As#n Ser Ser Val Val Tyr             20       #            25      #            30 Glu Ala Ala Asp Ala Ile Leu His Thr Pro Gl#y Cys Val Pro Cys Val         35           #        40          #        45 Arg Glu Gly Asn Ala Ser Arg Cys Trp Val Al#a Val Thr Pro Thr Val     50               #    55              #    60 Ala Thr Arg Asp Gly Lys Leu Pro Thr Thr Gl#n Leu Arg Arg His Ile 65                   #70                  #75                   #80 Asp Leu Leu Val Gly Ser Ala Thr Leu Cys Se#r Ala Leu Tyr Val Gly                 85   #                90  #                95 Asp Leu Cys Gly Ser Val Phe Leu Val Gly Gl#n Leu Phe Thr Phe Ser             100       #           105      #           110 Pro Arg His His Trp Thr Thr Gln Asp Cys As#n Cys Ser Ile Tyr Pro         115           #       120          #       125 Gly His Ile Thr Gly His Arg Met Ala Trp As#n Met Met Met Asn Trp     130               #   135              #   140 Ser Pro Thr Ala Ala Leu Val Val Ala Gln Le#u Leu Arg Ile Pro Gln 145                 1 #50                 1#55                 1 #60 Ala Ile Met Asp Met Ile Ala Gly Ala His Tr#p Gly Val Leu Ala Gly                 165   #               170  #               175 Ile Lys Tyr Phe Ser Met Val Gly Asn Trp Al#a Lys Val Leu Val Val             180       #           185      #           190 Leu Leu Leu Phe Ala         195 <210> SEQ ID NO 4<211> LENGTH: 350 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Hepatitis C virus E2 p#rotein sequence <400> SEQUENCE: 4Gly Val Asp Ala Glu Thr His Val Thr Gly Gl #y Asn Ala Gly Arg Thr 1               5   #                10   #                15Thr Ala Gly Leu Val Gly Leu Leu Thr Pro Gl #y Ala Lys Gln Asn Ile            20       #            25       #            30Gln Leu Ile Asn Thr Asn Gly Ser Trp His Il #e Asn Ser Thr Ala Leu        35           #        40           #        45Asn Cys Asn Glu Ser Leu Asn Thr Gly Trp Le #u Ala Gly Leu Phe Tyr    50               #    55               #    60Gln His Lys Phe Asn Ser Ser Gly Cys Pro Gl #u Arg Leu Ala Ser Cys65                   #70                   #75                   #80Arg Arg Leu Thr Asp Phe Ala Gln Gly Trp Gl #y Pro Ile Ser Tyr Ala                85   #                90   #                95Asn Gly Ser Gly Leu Asp Glu Arg Pro Tyr Cy #s Trp His Tyr Pro Pro            100       #           105       #           110Arg Pro Cys Gly Ile Val Pro Ala Lys Ser Va #l Cys Gly Pro Val Tyr        115           #       120           #       125Cys Phe Thr Pro Ser Pro Val Val Val Gly Th #r Thr Asp Arg Ser Gly    130               #   135               #   140Ala Pro Thr Tyr Ser Trp Gly Ala Asn Asp Th #r Asp Val Phe Val Leu145                 1 #50                 1 #55                 1 #60Asn Asn Thr Arg Pro Pro Leu Gly Asn Trp Ph #e Gly Cys Thr Trp Met                165   #               170   #               175Asn Ser Thr Gly Phe Thr Lys Val Cys Gly Al #a Pro Pro Cys Val Ile            180       #           185       #           190Gly Gly Val Gly Asn Asn Thr Leu Leu Cys Pr #o Thr Asp Cys Phe Arg        195           #       200           #       205Lys Tyr Pro Glu Ala Thr Tyr Ser Arg Cys Gl #y Ser Gly Pro Arg Ile    210               #   215               #   220Thr Pro Arg Cys Met Val Asp Tyr Pro Tyr Ar #g Leu Trp His Tyr Pro225                 2 #30                 2 #35                 2 #40Cys Thr Ile Asn Tyr Thr Ile Phe Lys Val Ar #g Met Tyr Val Gly Gly                245   #               250   #               255Val Glu His Arg Leu Glu Ala Ala Cys Asn Tr #p Thr Arg Gly Glu Arg            260       #           265       #           270Cys Asp Leu Glu Asp Arg Asp Arg Ser Glu Le #u Ser Pro Leu Leu Leu        275           #       280           #       285Ser Thr Thr Gln Trp Gln Val Leu Pro Cys Se #r Phe Thr Thr Leu Pro    290               #   295               #   300Ala Leu Ser Thr Gly Leu Ile His Leu His Gl #n Asn Ile Val Asp Val305                 3 #10                 3 #15                 3 #20Gln Tyr Leu Tyr Gly Val Gly Ser Ser Ile Al #a Ser Trp Ala Ile Lys                325   #               330   #               335Trp Glu Tyr Val Val Leu Leu Phe Leu Leu Le #u Ala Asp Ala            340       #           345       #           350<210> SEQ ID NO 5 <211> LENGTH: 315 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus NS2  #protein sequence<400> SEQUENCE: 5 Arg Val Cys Ser Cys Leu Trp Met Met Leu Le#u Ile Ser Gln Ala Glu  1               5   #                10  #                15 Ala Ala Leu Glu Asn Leu Val Ile Leu Asn Al#a Ala Ser Leu Ala Gly             20       #            25      #            30 Thr His Gly Leu Val Ser Phe Leu Val Phe Ph#e Cys Phe Ala Trp Tyr         35           #        40          #        45 Leu Lys Gly Arg Trp Val Pro Gly Ala Val Ty#r Ala Leu Tyr Gly Met     50               #    55              #    60 Trp Pro Leu Leu Leu Leu Leu Leu Ala Leu Pr#o Gln Arg Ala Tyr Ala 65                   #70                  #75                   #80 Leu Asp Thr Glu Val Ala Ala Ser Cys Gly Gl#y Val Val Leu Val Gly                 85   #                90  #                95 Leu Met Ala Leu Thr Leu Ser Pro Tyr Tyr Ly#s Arg Tyr Ile Ser Trp             100       #           105      #           110 Cys Met Trp Trp Leu Gln Tyr Phe Leu Thr Ar#g Val Glu Ala Gln Leu         115           #       120          #       125 His Val Trp Val Pro Pro Leu Asn Val Arg Gl#y Gly Arg Asp Ala Val     130               #   135              #   140 Ile Leu Leu Thr Cys Val Val His Pro Ala Le#u Val Phe Asp Ile Thr 145                 1 #50                 1#55                 1 #60 Lys Leu Leu Leu Ala Ile Phe Gly Pro Leu Tr#p Ile Leu Gln Ala Ser                 165   #               170  #               175 Leu Leu Lys Val Pro Tyr Phe Val Arg Val Gl#n Gly Leu Leu Arg Ile             180       #           185      #           190 Cys Ala Leu Ala Arg Lys Ile Ala Gly Gly Hi#s Tyr Val Gln Met Ala         195           #       200          #       205 Ile Ile Lys Leu Gly Ala Leu Thr Gly Thr Cy#s Val Tyr Asn His Leu     210               #   215              #   220 Ala Pro Leu Arg Asp Trp Ala His Asn Gly Le#u Arg Asp Leu Ala Val 225                 2 #30                 2#35                 2 #40 Ala Val Glu Pro Val Val Phe Ser Arg Met Gl#u Thr Lys Leu Ile Thr                 245   #               250  #               255 Trp Gly Ala Asp Thr Ala Ala Cys Gly Asp Il#e Ile Asn Gly Leu Pro             260       #           265      #           270 Val Ser Ala Arg Arg Gly Gln Glu Ile Leu Le#u Gly Pro Ala Asp Gly         275           #       280          #       285 Met Val Ser Lys Gly Trp Arg Leu Leu Ala Pr#o Ile Thr Ala Tyr Ala     290               #   295              #   300 Gln Gln Thr Arg Gly Leu Leu Gly Cys Ile Il #e305                 3 #10                 3 #15 <210> SEQ ID NO 6<211> LENGTH: 613 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Hepatitis C virus NS3 #protein sequence <400> SEQUENCE: 6Thr Ser Leu Thr Gly Arg Asp Lys Asn Gln Va #l Glu Gly Glu Val Gln 1               5   #                10   #                15Ile Val Ser Thr Ala Thr Gln Thr Phe Leu Al #a Thr Cys Ile Asn Gly            20       #            25       #            30Val Cys Trp Thr Val Tyr His Gly Ala Gly Th #r Arg Thr Ile Ala Ser        35           #        40           #        45Pro Lys Gly Pro Val Ile Gln Thr Tyr Thr As #n Val Asp Gln Asp Leu    50               #    55               #    60Val Gly Trp Pro Ala Pro Gln Gly Ser Arg Se #r Leu Thr Pro Cys Thr65                   #70                   #75                   #80Cys Gly Ser Ser Asp Leu Tyr Leu Val Thr Ar #g His Ala Asp Val Ile                85   #                90   #                95Pro Val Arg Arg Arg Gly Asp Ser Arg Gly Se #r Leu Leu Ser Pro Arg            100       #           105       #           110Pro Ile Ser Tyr Leu Lys Gly Ser Ser Gly Gl #y Pro Leu Leu Cys Pro        115           #       120           #       125Thr Gly His Ala Val Gly Leu Phe Arg Ala Al #a Val Cys Thr Arg Gly    130               #   135               #   140Val Ala Lys Ala Val Asp Phe Ile Pro Val Gl #u Asn Leu Glu Thr Thr145                 1 #50                 1 #55                 1 #60Met Arg Ser Pro Val Phe Thr Asp Asn Ser Se #r Pro Pro Ala Val Pro                165   #               170   #               175Gln Ser Phe Gln Val Ala His Leu His Ala Pr #o Thr Gly Ser Gly Lys            180       #           185       #           190Ser Thr Lys Val Pro Ala Ala Tyr Ala Ala Ly #s Gly Tyr Lys Val Leu        195           #       200           #       205Val Leu Asn Pro Ser Val Ala Ala Thr Leu Gl #y Phe Gly Ala Tyr Met    210               #   215               #   220Ser Lys Ala His Gly Val Asp Pro Asn Ile Ar #g Thr Gly Val Arg Thr225                 2 #30                 2 #35                 2 #40Ile Thr Thr Gly Ser Pro Ile Thr Tyr Ser Th #r Tyr Gly Lys Phe Leu                245   #               250   #               255Ala Asp Ala Gly Cys Ser Gly Gly Ala Tyr As #p Ile Ile Ile Cys Asp            260       #           265       #           270Glu Cys His Ser Thr Asp Ala Thr Ser Ile Se #r Gly Ile Gly Thr Val        275           #       280           #       285Leu Asp Gln Ala Glu Thr Ala Gly Ala Arg Le #u Val Val Leu Ala Thr    290               #   295               #   300Ala Thr Pro Pro Gly Ser Val Thr Val Ser Hi #s Pro Asn Ile Glu Glu305                 3 #10                 3 #15                 3 #20Val Ala Leu Ser Thr Thr Gly Glu Ile Pro Ph #e Tyr Gly Lys Ala Ile                325   #               330   #               335Pro Leu Glu Val Ile Lys Gly Gly Arg His Le #u Ile Phe Cys His Ser            340       #           345       #           350Lys Lys Lys Cys Asp Glu Leu Ala Ala Lys Le #u Val Ala Leu Gly Ile        355           #       360           #       365Asn Ala Val Ala Tyr Tyr Arg Gly Leu Asp Va #l Ser Val Ile Pro Thr    370               #   375               #   380Ser Gly Asp Val Val Val Val Ser Thr Asp Al #a Leu Met Thr Gly Phe385                 3 #90                 3 #95                 4 #00Thr Gly Asp Phe Asp Ser Val Ile Asp Cys As #n Thr Cys Val Thr Gln                405   #               410   #               415Thr Val Asp Phe Ser Leu Asp Pro Thr Phe Th #r Ile Glu Thr Thr Thr            420       #           425       #           430Leu Pro Gln Asp Ala Val Ser Arg Thr Gln Ar #g Arg Gly Arg Thr Gly        435           #       440           #       445Arg Gly Lys Pro Gly Ile Tyr Arg Phe Val Al #a Pro Gly Glu Arg Pro    450               #   455               #   460Ser Gly Met Phe Asp Ser Ser Val Leu Cys Gl #u Cys Tyr Asp Ala Gly465                 4 #70                 4 #75                 4 #80Cys Ala Trp Tyr Glu Leu Thr Pro Ala Glu Th #r Thr Val Arg Leu Arg                485   #               490   #               495Ala Tyr Met Asn Thr Pro Gly Leu Pro Val Cy #s Gln Asp His Leu Gly            500       #           505       #           510Phe Trp Glu Gly Val Phe Thr Gly Leu Thr Hi #s Ile Asp Ala His Phe        515           #       520           #       525Leu Ser Gln Thr Lys Gln Ser Gly Glu Asn Ph #e Pro Tyr Leu Val Ala    530               #   535               #   540Tyr Gln Ala Thr Val Cys Ala Arg Ala Gln Al #a Pro Pro Pro Ser Trp545                 5 #50                 5 #55                 5 #60Asp Gln Met Arg Lys Cys Leu Ile Arg Leu Ly #s Pro Thr Leu His Gly                565   #               570   #               575Pro Thr Pro Leu Leu Tyr Arg Leu Gly Ala Va #l Gln Asn Glu Val Thr            580       #           585       #           590Leu Thr His Pro Ile Thr Lys Tyr Ile Met Th #r Cys Met Ser Ala Asp        595           #       600           #       605Leu Glu Val Val Thr     610 <210> SEQ ID NO 7 <211> LENGTH: 54<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus NS4A  #protein sequence<400> SEQUENCE: 7 Ser Thr Trp Val Leu Val Gly Gly Val Leu Al#a Ala Leu Ala Ala Tyr  1               5   #                10  #                15 Cys Leu Ser Thr Gly Cys Val Val Ile Val Gl#y Arg Ile Val Leu Ser             20       #            25      #            30 Gly Lys Pro Ala Ile Ile Pro Asp Arg Glu Va#l Leu Tyr Gln Glu Phe         35           #        40          #        45 Asp Glu Met Glu Glu Cys     50 <210> SEQ ID NO 8<211> LENGTH: 260 <212> TYPE: PRT <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Hepatitis C virus NS4B #protein sequence <400> SEQUENCE: 8Ser Gln His Leu Pro Tyr Ile Glu Gln Gly Me #t Met Leu Ala Glu Gln 1               5   #                10   #                15Phe Lys Gln Lys Ala Leu Gly Leu Leu Gln Th #r Ala Ser Arg His Ala            20       #            25       #            30Glu Val Ile Thr Pro Ala Val Gln Thr Asn Tr #p Gln Lys Leu Glu Val        35           #        40           #        45Phe Trp Ala Lys His Met Trp Asn Phe Ile Se #r Gly Ile Gln Tyr Leu    50               #    55               #    60Ala Gly Leu Ser Thr Leu Pro Gly Asn Pro Al #a Ile Ala Ser Leu Met65                   #70                   #75                   #80Ala Phe Thr Ala Ala Val Thr Ser Pro Leu Th #r Thr Gly Gln Thr Leu                85   #                90   #                95Leu Phe Asn Ile Leu Gly Gly Trp Val Ala Al #a Gln Leu Ala Ala Pro            100       #           105       #           110Gly Ala Ala Thr Ala Phe Val Gly Ala Gly Le #u Ala Gly Ala Ala Leu        115           #       120           #       125Asp Ser Val Gly Leu Gly Lys Val Leu Val As #p Ile Leu Ala Gly Tyr    130               #   135               #   140Gly Ala Gly Val Ala Gly Ala Leu Val Ala Ph #e Lys Ile Met Ser Gly145                 1 #50                 1 #55                 1 #60Glu Val Pro Ser Thr Glu Asp Leu Val Asn Le #u Leu Pro Ala Ile Leu                165   #               170   #               175Ser Pro Gly Ala Leu Ala Val Gly Val Val Ph #e Ala Ser Ile Leu Arg            180       #           185       #           190Arg Arg Val Gly Pro Gly Glu Gly Ala Val Gl #n Trp Met Asn Arg Leu        195           #       200           #       205Ile Ala Phe Ala Ser Arg Gly Asn His Val Se #r Pro Thr His Tyr Val    210               #   215               #   220Pro Glu Ser Asp Ala Ala Ala Arg Val Thr Al #a Ile Leu Ser Ser Leu225                 2 #30                 2 #35                 2 #40Thr Val Thr Gln Leu Leu Arg Arg Leu His Gl #n Trp Ile Ser Ser Glu                245   #               250   #               255Cys Thr Thr Pro             260 <210> SEQ ID NO 9 <211> LENGTH: 1040<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus NS5A/B  #protein sequence<400> SEQUENCE: 9 Cys Ser Gly Ser Trp Leu Arg Asp Ile Trp As#p Trp Ile Cys Glu Val  1               5   #                10  #                15 Leu Ser Asp Phe Lys Thr Trp Leu Lys Ala Ly#s Leu Met Pro Gln Leu             20       #            25      #            30 Pro Gly Ile Pro Phe Val Ser Cys Gln Arg Gl#y Tyr Arg Gly Val Trp         35           #        40          #        45 Arg Gly Asp Gly Ile Met His Thr Arg Cys Hi#s Cys Gly Ala Glu Ile     50               #    55              #    60 Thr Gly His Val Lys Asn Gly Thr Met Arg Il#e Val Gly Pro Arg Thr 65                   #70                  #75                   #80 Cys Lys Asn Met Trp Ser Gly Thr Phe Phe Il#e Asn Ala Tyr Thr Thr                 85   #                90  #                95 Gly Pro Cys Thr Pro Leu Pro Ala Pro Asn Ty#r Lys Phe Ala Leu Trp             100       #           105      #           110 Arg Val Ser Ala Glu Glu Tyr Val Glu Ile Ar#g Arg Val Gly Asp Phe         115           #       120          #       125 His Tyr Val Ser Gly Met Thr Thr Asp Asn Le#u Lys Cys Pro Cys Gln     130               #   135              #   140 Ile Pro Ser Pro Glu Phe Phe Thr Glu Leu As#p Gly Val Arg Leu His 145                 1 #50                 1#55                 1 #60 Arg Phe Ala Pro Pro Cys Lys Pro Leu Leu Ar#g Glu Glu Val Ser Phe                 165   #               170  #               175 Arg Val Gly Leu His Glu Tyr Pro Val Gly Se#r Gln Leu Pro Cys Glu             180       #           185      #           190 Pro Glu Pro Asp Val Ala Val Leu Thr Ser Me#t Leu Thr Asp Pro Ser         195           #       200          #       205 His Ile Thr Ala Glu Ala Ala Gly Arg Arg Le#u Ala Arg Gly Ser Pro     210               #   215              #   220 Pro Ser Met Ala Ser Ser Ser Ala Ser Gln Le#u Ser Ala Pro Ser Leu 225                 2 #30                 2#35                 2 #40 Lys Ala Thr Cys Thr Ala Asn His Asp Ser Pr#o Asp Ala Glu Leu Ile                 245   #               250  #               255 Glu Ala Asn Leu Leu Trp Arg Gln Glu Met Gl#y Gly Asn Ile Thr Arg             260       #           265      #           270 Val Glu Ser Glu Asn Lys Val Val Ile Leu As#p Ser Phe Asp Pro Leu         275           #       280          #       285 Val Ala Glu Glu Asp Glu Arg Glu Val Ser Va#l Pro Ala Glu Ile Leu     290               #   295              #   300 Arg Lys Ser Arg Arg Phe Ala Pro Ala Leu Pr#o Val Trp Ala Arg Pro 305                 3 #10                 3#15                 3 #20 Asp Tyr Asn Pro Leu Leu Val Glu Thr Trp Ly#s Lys Pro Asp Tyr Glu                 325   #               330  #               335 Pro Pro Val Val His Gly Cys Pro Leu Pro Pr#o Pro Arg Ser Pro Pro             340       #           345      #           350 Val Pro Pro Pro Arg Lys Lys Arg Thr Val Va#l Leu Thr Glu Ser Thr         355           #       360          #       365 Leu Pro Thr Ala Leu Ala Glu Leu Ala Thr Ly#s Ser Phe Gly Ser Ser     370               #   375              #   380 Ser Thr Ser Gly Ile Thr Gly Asp Asn Thr Th#r Thr Ser Ser Glu Pro 385                 3 #90                 3#95                 4 #00 Ala Pro Ser Gly Cys Pro Pro Asp Ser Asp Va#l Glu Ser Tyr Ser Ser                 405   #               410  #               415 Met Pro Pro Leu Glu Gly Glu Pro Gly Asp Pr#o Asp Leu Ser Asp Gly             420       #           425      #           430 Ser Trp Ser Thr Val Ser Ser Gly Ala Asp Th#r Glu Asp Val Val Cys         435           #       440          #       445 Cys Ser Met Ser Tyr Ser Trp Thr Gly Ala Le#u Val Thr Pro Cys Ala     450               #   455              #   460 Ala Glu Glu Gln Lys Leu Pro Ile Asn Ala Le#u Ser Asn Ser Leu Leu 465                 4 #70                 4#75                 4 #80 Arg His His Asn Leu Val Tyr Ser Thr Thr Se#r Arg Ser Ala Cys Gln                 485   #               490  #               495 Arg Lys Lys Lys Val Thr Phe Asp Arg Leu Gl#n Val Leu Asp Ser His             500       #           505      #           510 Tyr Gln Asp Val Leu Lys Glu Val Lys Ala Al#a Ala Ser Lys Val Lys         515           #       520          #       525 Ala Asn Leu Leu Ser Val Glu Glu Ala Cys Se#r Leu Ala Pro Pro His     530               #   535              #   540 Ser Ala Lys Ser Lys Phe Gly Tyr Gly Ala Ly#s Asp Val Arg Cys His 545                 5 #50                 5#55                 5 #60 Ala Arg Lys Ala Val Ala His Ile Asn Ser Va#l Trp Lys Asp Leu Leu                 565   #               570  #               575 Glu Asp Ser Val Thr Pro Ile Asp Thr Thr Il#e Met Ala Lys Asn Glu             580       #           585      #           590 Val Phe Cys Val Gln Pro Glu Lys Gly Gly Ar#g Lys Pro Ala Arg Leu         595           #       600          #       605 Ile Val Phe Pro Asp Leu Gly Val Arg Val Cy#s Glu Lys Met Ala Leu     610               #   615              #   620 Tyr Asp Val Val Ser Lys Leu Pro Leu Ala Va#l Met Gly Ser Ser Tyr 625                 6 #30                 6#35                 6 #40 Gly Phe Gln Tyr Ser Pro Gly Gln Arg Val Gl#u Phe Leu Val Gln Ala                 645   #               650  #               655 Trp Lys Ser Lys Lys Thr Pro Met Gly Leu Se#r Tyr Asp Thr Arg Cys             660       #           665      #           670 Phe Asp Ser Thr Val Thr Glu Ser Asp Ile Ar#g Thr Glu Glu Ala Ile         675           #       680          #       685 Tyr Gln Cys Cys Asp Leu Asp Pro Gln Ala Ar#g Val Ala Ile Lys Ser     690               #   695              #   700 Leu Thr Glu Arg Leu Tyr Val Gly Gly Pro Le#u Thr Asn Ser Arg Gly 705                 7 #10                 7#15                 7 #20 Glu Asn Cys Gly Tyr Arg Arg Cys Arg Ala Se#r Arg Val Leu Thr Thr                 725   #               730  #               735 Ser Cys Gly Asn Thr Leu Thr Arg Tyr Ile Ly#s Ala Arg Ala Ala Cys             740       #           745      #           750 Arg Ala Ala Gly Leu Gln Asp Cys Thr Met Le#u Val Cys Gly Asp Asp         755           #       760          #       765 Leu Val Val Ile Cys Glu Ser Ala Gly Val Gl#n Glu Asp Ala Ala Ser     770               #   775              #   780 Leu Arg Ala Phe Thr Glu Ala Met Thr Arg Ty#r Ser Ala Pro Pro Gly 785                 7 #90                 7#95                 8 #00 Asp Pro Pro Gln Pro Glu Tyr Asp Leu Glu Le#u Ile Thr Ser Cys Ser                 805   #               810  #               815 Ser Asn Val Ser Val Ala His Asp Gly Ala Gl#y Lys Arg Val Tyr Tyr             820       #           825      #           830 Leu Thr Arg Asp Pro Thr Thr Pro Leu Ala Ar#g Ala Ala Trp Glu Thr         835           #       840          #       845 Ala Arg His Thr Pro Val Asn Ser Trp Leu Gl#y Asn Ile Ile Met Phe     850               #   855              #   860 Ala Pro Thr Leu Trp Ala Arg Met Ile Leu Me#t Thr His Phe Phe Ser 865                 8 #70                 8#75                 8 #80 Val Leu Ile Ala Arg Asp Gln Leu Glu Gln Al#a Leu Asn Cys Glu Ile                 885   #               890  #               895 Tyr Gly Ala Cys Tyr Ser Ile Glu Pro Leu As#p Leu Pro Pro Ile Ile             900       #           905      #           910 Gln Arg Leu His Gly Leu Ser Ala Phe Ser Le#u His Ser Tyr Ser Pro         915           #       920          #       925 Gly Glu Ile Asn Arg Val Ala Ala Cys Leu Ar#g Lys Leu Gly Val Pro     930               #   935              #   940 Pro Leu Arg Ala Trp Arg His Arg Ala Trp Se#r Val Arg Ala Arg Leu 945                 9 #50                 9#55                 9 #60 Leu Ala Arg Gly Gly Lys Ala Ala Ile Cys Gl#y Lys Tyr Leu Phe Asn                 965   #               970  #               975 Trp Ala Val Arg Thr Lys Leu Lys Leu Thr Pr#o Ile Thr Ala Ala Gly             980       #           985      #           990 Arg Leu Asp Leu Ser Gly Trp Phe Thr Ala Gl#y Tyr Ser Gly Gly Asp         995           #       1000          #      1005 Ile Tyr His Ser Val Ser His Ala Arg Pro Ar#g Trp Phe Trp Phe Cys     1010              #   1015              #  1020 Leu Leu Leu Leu Ala Ala Gly Val Gly Ile Ty#r Leu Leu Pro Asn Arg 1025                 #1030                103#5                1040 <210> SEQ ID NO 10 <211> LENGTH: 226<212> TYPE: PRT <213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis B virus S an #tigen (HBsAg) sequence<400> SEQUENCE: 10 Met Glu Asn Ile Thr Ser Gly Phe Leu Gly Pr#o Leu Leu Val Leu Gln  1               5   #                10  #                15 Ala Gly Phe Phe Leu Leu Thr Arg Ile Leu Th#r Ile Pro Gln Ser Leu             20       #            25      #            30 Asp Ser Trp Trp Thr Ser Leu Asn Phe Leu Gl#y Gly Thr Thr Val Cys         35           #        40          #        45 Leu Gly Gln Asn Ser Gln Ser Pro Thr Ser As#n His Ser Pro Thr Ser     50               #    55              #    60 Cys Pro Pro Thr Cys Pro Gly Tyr Arg Trp Me#t Cys Leu Arg Arg Phe 65                   #70                  #75                   #80 Ile Ile Phe Leu Phe Ile Leu Leu Leu Cys Le#u Ile Phe Leu Leu Val                 85   #                90  #                95 Leu Leu Asp Tyr Gln Gly Met Leu Pro Val Cy#s Pro Leu Ile Pro Gly             100       #           105      #           110 Ser Ser Thr Thr Ser Thr Gly Pro Cys Arg Th#r Cys Met Thr Thr Ala         115           #       120          #       125 Gln Gly Thr Ser Met Tyr Pro Ser Cys Cys Cy#s Thr Lys Pro Ser Asp     130               #   135              #   140 Gly Asn Cys Thr Cys Ile Pro Ile Pro Ser Se#r Trp Ala Phe Gly Lys 145                 1 #50                 1#55                 1 #60 Phe Leu Trp Glu Trp Ala Ser Ala Arg Phe Se#r Trp Leu Ser Leu Leu                 165   #               170  #               175 Val Pro Phe Val Gln Trp Phe Val Gly Leu Se#r Pro Thr Val Trp Leu             180       #           185      #           190 Ser Val Ile Trp Met Met Trp Tyr Trp Gly Pr#o Ser Leu Tyr Ser Ile         195           #       200          #       205 Leu Ser Pro Phe Leu Pro Leu Leu Pro Ile Ph#e Phe Cys Leu Trp Val     210               #   215              #   220 Tyr Ile 225 <210> SEQ ID NO 11 <211> LENGTH: 212 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis B virus C an #tigen and e antigen      (HBcAg/HBeAg) sequence <400> SEQUENCE: 11Met Gln Leu Phe His Leu Cys Leu Ile Ile Se #r Cys Ser Cys Pro Thr 1               5   #                10   #                15Val Gln Ala Ser Lys Leu Cys Leu Gly Trp Le #u Trp Gly Met Asp Ile            20       #            25       #            30Asp Pro Tyr Lys Glu Phe Gly Ala Thr Val Gl #u Leu Leu Ser Phe Leu        35           #        40           #        45Pro Ser Asp Phe Phe Pro Ser Val Arg Asp Le #u Leu Asp Thr Ala Ser    50               #    55               #    60Ala Leu Tyr Arg Glu Ala Leu Glu Ser Pro Gl #u His Cys Ser Pro His65                   #70                   #75                   #80His Thr Ala Leu Arg Gln Ala Ile Leu Cys Tr #p Gly Glu Leu Met Thr                85   #                90   #                95Leu Ala Thr Trp Val Gly Val Asn Leu Glu As #p Pro Ala Ser Arg Asp            100       #           105       #           110Leu Val Val Ser Tyr Val Asn Thr Asn Met Gl #y Leu Lys Phe Arg Gln        115           #       120           #       125Leu Leu Trp Phe His Ile Ser Cys Leu Thr Ph #e Gly Arg Glu Thr Val    130               #   135               #   140Ile Glu Tyr Leu Val Ser Phe Gly Val Trp Il #e Arg Thr Pro Pro Ala145                 1 #50                 1 #55                 1 #60Tyr Arg Pro Pro Asn Ala Pro Ile Leu Ser Th #r Leu Pro Glu Thr Thr                165   #               170   #               175Val Val Arg Arg Arg Gly Arg Ser Pro Arg Ar #g Arg Thr Pro Ser Pro            180       #           185       #           190Arg Arg Arg Arg Ser Gln Ser Pro Arg Arg Ar #g Arg Ser Gln Ser Arg        195           #       200           #       205 Glu Ser Gln Cys    210 <210> SEQ ID NO 12 <211> LENGTH: 2227 <212> TYPE: PRT<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis A virus sequenc #e <400> SEQUENCE: 12Met Asn Met Ser Lys Gln Gly Ile Phe Gln Th #r Val Gly Ser Gly Leu 1               5   #                10   #                15Asp His Ile Leu Ser Leu Ala Asp Ile Glu Gl #u Glu Gln Met Ile Gln            20       #            25       #            30Ser Val Asp Arg Thr Ala Val Thr Gly Ala Se #r Tyr Phe Thr Ser Val        35           #        40           #        45Asp Gln Ser Ser Val His Thr Ala Glu Val Gl #y Ser His Gln Ile Glu    50               #    55               #    60Pro Leu Lys Thr Ser Val Asp Lys Pro Gly Se #r Lys Lys Thr Gln Gly65                   #70                   #75                   #80Glu Lys Phe Phe Leu Ile His Ser Ala Asp Tr #p Leu Thr Thr His Ala                85   #                90   #                95Leu Phe His Glu Val Ala Lys Leu Asp Val Va #l Lys Leu Leu Tyr Asn            100       #           105       #           110Glu Gln Phe Ala Val Gln Gly Leu Leu Arg Ty #r His Thr Tyr Ala Arg        115           #       120           #       125Phe Gly Ile Glu Ile Gln Val Gln Ile Asn Pr #o Thr Pro Phe Gln Gln    130               #   135               #   140Gly Gly Leu Ile Cys Ala Met Val Pro Gly As #p Gln Ser Tyr Gly Ser145                 1 #50                 1 #55                 1 #60Ile Ala Ser Leu Thr Val Tyr Pro His Gly Le #u Leu Asn Cys Asn Ile                165   #               170   #               175Asn Asn Val Val Arg Ile Lys Val Pro Phe Il #e Tyr Thr Arg Gly Ala            180       #           185       #           190Tyr His Phe Lys Asp Pro Gln Tyr Pro Val Tr #p Glu Leu Thr Ile Arg        195           #       200           #       205Val Trp Ser Glu Leu Asn Ile Gly Thr Gly Th #r Ser Ala Tyr Thr Ser    210               #   215               #   220Leu Asn Val Leu Ala Arg Phe Thr Asp Leu Gl #u Leu His Gly Leu Thr225                 2 #30                 2 #35                 2 #40Pro Leu Ser Thr Gln Met Met Arg Asn Glu Ph #e Arg Val Ser Thr Thr                245   #               250   #               255Glu Asn Val Val Asn Leu Ser Asn Tyr Glu As #p Ala Arg Ala Lys Met            260       #           265       #           270Ser Phe Ala Leu Asp Gln Glu Asp Trp Lys Se #r Asp Pro Ser Gln Gly        275           #       280           #       285Gly Gly Ile Lys Ile Thr His Phe Thr Thr Tr #p Thr Ser Ile Pro Thr    290               #   295               #   300Leu Ala Ala Gln Phe Pro Phe Asn Ala Ser As #p Ser Val Gly Gln Gln305                 3 #10                 3 #15                 3 #20Ile Lys Val Ile Pro Val Asp Pro Tyr Phe Ph #e Gln Met Thr Asn Thr                325   #               330   #               335Asn Pro Asp Gln Lys Cys Ile Thr Ala Leu Al #a Ser Ile Cys Gln Met            340       #           345       #           350Phe Cys Phe Trp Arg Gly Asp Leu Val Phe As #p Phe Gln Val Phe Pro        355           #       360           #       365Thr Lys Tyr His Ser Gly Arg Leu Leu Phe Cy #s Phe Val Pro Gly Asn    370               #   375               #   380Glu Leu Ile Asp Val Thr Gly Ile Thr Leu Ly #s Gln Ala Thr Thr Ala385                 3 #90                 3 #95                 4 #00Pro Cys Ala Val Met Asp Ile Thr Gly Val Gl #n Ser Thr Leu Arg Phe                405   #               410   #               415Arg Val Pro Trp Ile Ser Asp Thr Pro Tyr Ar #g Val Asn Arg Tyr Thr            420       #           425       #           430Lys Ser Ala His Gln Lys Gly Glu Tyr Thr Al #a Ile Gly Lys Leu Ile        435           #       440           #       445Val Tyr Cys Tyr Asn Arg Leu Thr Ser Pro Se #r Asn Val Ala Ser His    450               #   455               #   460Val Arg Val Asn Val Tyr Leu Ser Ala Ile As #n Leu Glu Cys Phe Ala465                 4 #70                 4 #75                 4 #80Pro Leu Tyr His Ala Met Asp Val Thr Thr Gl #n Val Gly Asp Asp Ser                485   #               490   #               495Gly Gly Phe Ser Thr Thr Val Ser Thr Glu Gl #n Asn Val Pro Asp Pro            500       #           505       #           510Gln Val Gly Ile Thr Thr Met Arg Asp Leu Ly #s Gly Lys Ala Asn Arg        515           #       520           #       525Gly Lys Met Asp Val Ser Gly Val Gln Ala Pr #o Arg Gly Ser Tyr Gln    530               #   535               #   540Gln Gln Leu Asn Asp Pro Val Leu Ala Lys Ly #s Val Pro Glu Thr Phe545                 5 #50                 5 #55                 5 #60Pro Glu Leu Lys Pro Gly Glu Ser Arg His Th #r Ser Asp His Met Ser                565   #               570   #               575Ile Tyr Lys Phe Met Gly Arg Ser His Phe Le #u Cys Thr Phe Thr Phe            580       #           585       #           590Asn Ser Asn Asn Lys Glu Tyr Thr Phe Pro Il #e Thr Leu Ser Ser Thr        595           #       600           #       605Ser Asn Pro Pro His Gly Leu Pro Ser Thr Le #u Arg Trp Phe Phe Asn    610               #   615               #   620Leu Phe Gln Leu Tyr Arg Gly Pro Leu Asp Le #u Thr Ile Ile Ile Thr625                 6 #30                 6 #35                 6 #40Gly Ala Thr Asp Val Asp Gly Met Ala Trp Ph #e Thr Pro Val Gly Leu                645   #               650   #               655Ala Val Asp Pro Trp Val Glu Lys Glu Ser Al #a Leu Ser Ile Asp Tyr            660       #           665       #           670Lys Thr Ala Leu Gly Ala Val Arg Phe Asn Th #r Arg Arg Thr Gly Asn        675           #       680           #       685Ile Gln Ile Arg Leu Pro Trp Tyr Ser Tyr Le #u Tyr Ala Val Ser Gly    690               #   695               #   700Ala Leu Asp Gly Leu Gly Asp Lys Thr Asp Se #r Thr Phe Gly Leu Phe705                 7 #10                 7 #15                 7 #20Leu Phe Glu Ile Ala Asn Tyr Asn His Ser As #p Glu Tyr Leu Ser Phe                725   #               730   #               735Ser Cys Tyr Leu Ser Val Thr Glu Gln Ser Gl #u Phe Tyr Phe Pro Arg            740       #           745       #           750Ala Pro Leu Asn Ser Asn Ala Met Leu Ser Th #r Glu Ser Met Met Ser        755           #       760           #       765Arg Ile Ala Ala Gly Asp Leu Glu Ser Ser Va #l Asp Asp Pro Arg Ser    770               #   775               #   780Glu Glu Asp Arg Arg Phe Glu Ser His Ile Gl #u Cys Arg Lys Pro Tyr785                 7 #90                 7 #95                 8 #00Lys Glu Leu Arg Leu Glu Val Gly Lys Gln Ar #g Leu Lys Tyr Ala Gln                805   #               810   #               815Glu Glu Leu Ser Asn Glu Val Leu Pro Pro Pr #o Arg Lys Met Lys Gly            820       #           825       #           830Leu Phe Ser Gln Ala Lys Ile Ser Leu Phe Ty #r Thr Glu Glu His Glu        835           #       840           #       845Ile Met Lys Phe Ser Trp Arg Gly Val Thr Al #a Asp Thr Arg Ala Leu    850               #   855               #   860Arg Arg Phe Gly Phe Ser Leu Ala Ala Gly Ar #g Ser Val Trp Thr Leu865                 8 #70                 8 #75                 8 #80Glu Met Asp Ala Gly Val Leu Thr Gly Arg Le #u Ile Arg Leu Asn Asp                885   #               890   #               895Glu Lys Trp Thr Glu Met Lys Asp Asp Lys Il #e Val Ser Leu Ile Glu            900       #           905       #           910Lys Phe Thr Ser Asn Lys Tyr Trp Ser Lys Va #l Asn Phe Pro His Gly        915           #       920           #       925Met Leu Asp Leu Glu Glu Ile Ala Ala Asn Se #r Lys Asp Phe Pro Asn    930               #   935               #   940Met Ser Glu Thr Asp Leu Cys Phe Leu Leu Hi #s Trp Leu Asn Pro Lys945                 9 #50                 9 #55                 9 #60Lys Ile Asn Leu Ala Asp Arg Met Leu Gly Le #u Ser Gly Val Gln Glu                965   #               970   #               975Ile Lys Glu Gln Gly Val Gly Leu Ile Ala Gl #u Cys Arg Thr Phe Leu            980       #           985       #           990Asp Ser Ile Ala Gly Thr Leu Lys Ser Met Me #t Phe Gly Phe His His        995           #       1000           #      1005Ser Val Thr Val Glu Ile Ile Asn Thr Val Le #u Cys Phe Val Lys Ser    1010              #   1015               #  1020Gly Ile Leu Leu Tyr Val Ile Gln Gln Leu As #n Gln Asp Glu His Ser1025                1030 #                1035  #               1040His Ile Ile Gly Leu Leu Arg Val Met Asn Ty #r Ala Asp Ile Gly Cys                1045  #               1050   #              1055Ser Val Ile Ser Cys Gly Lys Val Phe Ser Ly #s Met Leu Glu Thr Val            1060      #           1065       #          1070Phe Asn Trp Gln Met Asp Ser Arg Met Met Gl #u Leu Arg Thr Gln Ser        1075          #       1080           #      1085Phe Ser Asn Trp Leu Arg Asp Ile Cys Ser Gl #y Ile Thr Ile Phe Lys    1090              #   1095               #  1100Ser Phe Lys Asp Ala Ile Tyr Trp Leu Tyr Th #r Lys Leu Lys Asp Phe1105                1110 #                1115  #               1120Tyr Glu Val Asn Tyr Gly Lys Lys Lys Asp Il #e Leu Asn Ile Leu Lys                1125  #               1130   #              1135Asp Asn Gln Gln Lys Ile Glu Lys Ala Ile Gl #u Glu Ala Asp Asn Phe            1140      #           1145       #          1150Cys Ile Leu Gln Ile Gln Asp Val Glu Lys Ph #e Asp Gln Tyr Gln Lys        1155          #       1160           #      1165Gly Val Asp Leu Ile Gln Lys Leu Arg Thr Va #l His Ser Met Ala Gln    1170              #   1175               #  1180Val Asp Pro Asn Leu Gly Val His Leu Ser Pr #o Leu Arg Asp Cys Ile1185                1190 #                1195  #               1200Ala Arg Val His Gln Lys Leu Lys Asn Leu Gl #y Ser Ile Asn Gln Ala                1205  #               1210   #              1215Met Val Thr Arg Cys Glu Pro Val Val Cys Ty #r Leu Tyr Gly Lys Arg            1220      #           1225       #          1230Gly Gly Gly Lys Ser Leu Thr Ser Ile Ala Le #u Ala Thr Lys Ile Cys        1235          #       1240           #      1245Lys His Tyr Gly Val Glu Pro Glu Lys Asn Il #e Tyr Thr Lys Pro Val    1250              #   1255               #  1260Ala Ser Asp Tyr Trp Asp Gly Tyr Ser Gly Gl #n Leu Val Cys Ile Ile1265                1270 #                1275  #               1280Asp Asp Ile Gly Gln Asn Thr Thr Asp Glu As #p Trp Ser Asp Phe Cys                1285  #               1290   #              1295Gln Leu Val Ser Gly Cys Pro Met Arg Leu As #n Met Ala Ser Leu Glu            1300      #           1305       #          1310Glu Lys Gly Arg His Phe Ser Ser Pro Phe Il #e Ile Ala Thr Ser Asn        1315          #       1320           #      1325Trp Ser Asn Pro Ser Pro Lys Thr Val Tyr Va #l Lys Glu Ala Ile Asp    1330              #   1335               #  1340Arg Arg Leu His Phe Lys Val Glu Val Lys Pr #o Ala Ser Phe Phe Lys1345                1350 #                1355  #               1360Asn Pro His Asn Asp Met Leu Asn Val Asn Le #u Ala Lys Thr Asn Asp                1365  #               1370   #              1375Ala Ile Lys Asp Met Ser Cys Val Asp Leu Il #e Met Asp Gly His Asn            1380      #           1385       #          1390Ile Ser Leu Met Asp Leu Leu Ser Ser Leu Va #l Met Thr Val Glu Ile        1395          #       1400           #      1405Arg Lys Gln Asn Met Ser Glu Phe Met Glu Le #u Trp Ser Gln Gly Ile    1410              #   1415               #  1420Ser Asp Asp Asp Asn Asp Ser Ala Val Ala Gl #u Phe Phe Gln Ser Phe1425                1430 #                1435  #               1440Pro Ser Gly Glu Pro Ser Asn Trp Lys Leu Se #r Ser Phe Phe Gln Ser                1445  #               1450   #              1455Val Thr Asn His Lys Trp Val Ala Val Gly Al #a Ala Val Gly Ile Leu            1460      #           1465       #          1470Gly Val Leu Val Gly Gly Trp Phe Val Tyr Ly #s His Phe Ser Arg Lys        1475          #       1480           #      1485Glu Glu Glu Pro Ile Pro Ala Glu Gly Val Ty #r His Gly Val Thr Lys    1490              #   1495               #  1500Pro Lys Gln Val Ile Lys Leu Asp Ala Asp Pr #o Val Glu Ser Gln Ser1505                1510 #                1515  #               1520Thr Leu Glu Ile Ala Gly Leu Val Arg Lys As #n Leu Val Gln Phe Gly                1525  #               1530   #              1535Val Gly Glu Lys Asn Gly Cys Val Arg Trp Va #l Met Asn Ala Leu Gly            1540      #           1545       #          1550Val Lys Asp Asp Trp Leu Leu Val Pro Ser Hi #s Ala Tyr Lys Phe Glu        1555          #       1560           #      1565Lys Asp Tyr Glu Met Met Glu Phe Tyr Phe As #n Arg Gly Gly Thr Tyr    1570              #   1575               #  1580Tyr Ser Ile Ser Ala Gly Asn Val Val Ile Gl #n Ser Leu Asp Val Gly1585                1590 #                1595  #               1600Phe Gln Asp Val Val Leu Met Lys Val Pro Th #r Ile Pro Lys Phe Arg                1605  #               1610   #              1615Asp Ile Thr Gln His Phe Ile Lys Lys Gly As #p Val Pro Arg Ala Leu            1620      #           1625       #          1630Asn Arg Leu Ala Thr Leu Val Thr Thr Val As #n Gly Thr Pro Met Leu        1635          #       1640           #      1645Ile Ser Glu Gly Pro Leu Lys Met Glu Glu Ly #s Ala Thr Tyr Val His    1650              #   1655               #  1660Lys Lys Asn Asp Gly Thr Thr Val Asp Leu Th #r Val Asp Gln Ala Trp1665                1670 #                1675  #               1680Arg Gly Lys Gly Glu Gly Leu Pro Gly Met Cy #s Gly Gly Ala Leu Val                1685  #               1690   #              1695Ser Ser Asn Gln Ser Ile Gln Asn Ala Ile Le #u Gly Ile His Val Ala            1700      #           1705       #          1710Gly Gly Asn Ser Ile Leu Val Ala Lys Leu Va #l Thr Gln Glu Met Phe        1715          #       1720           #      1725Gln Asn Ile Asp Lys Lys Ile Glu Ser Gln Ar #g Ile Met Lys Val Glu    1730              #   1735               #  1740Phe Thr Gln Cys Ser Met Asn Val Val Ser Ly #s Thr Leu Phe Arg Lys1745                1750 #                1755  #               1760Ser Pro Ile His His His Ile Asp Lys Thr Me #t Ile Asn Phe Pro Ala                1765  #               1770   #              1775Ala Met Pro Phe Ser Lys Ala Glu Ile Asp Pr #o Met Ala Met Met Leu            1780      #           1785       #          1790Ser Lys Tyr Ser Leu Pro Ile Val Glu Glu Pr #o Glu Asp Tyr Lys Glu        1795          #       1800           #      1805Ala Ser Val Phe Tyr Gln Asn Lys Ile Val Gl #y Lys Thr Gln Leu Val    1810              #   1815               #  1820Asp Asp Phe Leu Asp Leu Asp Met Ala Ile Th #r Gly Ala Pro Gly Ile1825                1830 #                1835  #               1840Asp Ala Ile Asn Met Asp Ser Ser Pro Gly Ph #e Pro Tyr Val Gln Glu                1845  #               1850   #              1855Lys Leu Thr Lys Arg Asp Leu Ile Trp Leu As #p Glu Asn Gly Leu Leu            1860      #           1865       #          1870Leu Gly Val His Pro Arg Leu Ala Gln Arg Il #e Leu Phe Asn Thr Val        1875          #       1880           #      1885Met Met Glu Asn Cys Ser Asp Leu Asp Val Va #l Phe Thr Thr Cys Pro    1890              #   1895               #  1900Lys Asp Glu Leu Arg Pro Leu Glu Lys Val Le #u Glu Ser Lys Thr Arg1905                1910 #                1915  #               1920Ala Ile Asp Ala Cys Pro Leu Asp Tyr Thr Il #e Leu Cys Arg Met Tyr                1925  #               1930   #              1935Trp Gly Pro Ala Ile Ser Tyr Phe His Leu As #n Pro Gly Phe His Thr            1940      #           1945       #          1950Gly Val Ala Ile Gly Ile Asp Pro Asp Arg Gl #n Trp Asp Glu Leu Phe        1955          #       1960           #      1965Lys Thr Met Ile Arg Phe Gly Asp Val Gly Le #u Asp Leu Asp Phe Ser    1970              #   1975               #  1980Ala Phe Asp Ala Ser Leu Ser Pro Phe Met Il #e Arg Glu Ala Gly Arg1985                1990 #                1995  #               2000Ile Met Ser Glu Leu Ser Gly Thr Pro Ser Hi #s Phe Gly Thr Ala Leu                2005  #               2010   #              2015Ile Asn Thr Ile Ile Tyr Ser Lys His Leu Le #u Tyr Asn Cys Cys Tyr            2020      #           2025       #          2030His Val Cys Gly Ser Met Pro Ser Gly Ser Pr #o Cys Thr Ala Leu Leu        2035          #       2040           #      2045Asn Ser Ile Ile Asn Asn Ile Asn Leu Tyr Ty #r Val Phe Ser Lys Ile    2050              #   2055               #  2060Phe Gly Lys Ser Pro Val Phe Phe Cys Gln Al #a Leu Arg Ile Leu Cys2065                2070 #                2075  #               2080Tyr Gly Asp Asp Val Leu Ile Val Phe Ser Ar #g Asp Val Gln Ile Asp                2085  #               2090   #              2095Asn Leu Asp Leu Ile Gly Gln Lys Ile Val As #p Glu Phe Lys Lys Leu            2100      #           2105       #          2110Gly Met Thr Ala Thr Ser Ala Asp Lys Asn Va #l Pro Gln Leu Lys Pro        2115          #       2120           #      2125Val Ser Glu Leu Thr Phe Leu Lys Arg Ser Ph #e Asn Leu Val Glu Asp    2130              #   2135               #  2140Arg Ile Arg Pro Ala Ile Ser Glu Lys Thr Il #e Trp Ser Leu Met Ala2145                2150 #                2155  #               2160Trp Gln Arg Ser Asn Ala Glu Phe Glu Gln As #n Leu Glu Asn Ala Gln                2165  #               2170   #              2175Trp Phe Ala Phe Met His Gly Tyr Glu Phe Ty #r Gln Lys Phe Tyr Tyr            2180      #           2185       #          2190Phe Val Gln Ser Cys Leu Glu Lys Glu Met Il #e Glu Tyr Arg Leu Lys        2195          #       2200           #      2205Ser Tyr Asp Trp Trp Arg Met Arg Phe Tyr As #p Gln Cys Phe Ile Cys    2210              #   2215               #  2220 Asp Leu Ser 2225<210> SEQ ID NO 13 <211> LENGTH: 9416 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis C virus sequenc #e <400> SEQUENCE: 13gccagccccc tgatgggggc gacactccac catgaatcac tcccctgtga gg#aactactg     60tcttcacgca gaaagcgtct agccatggcg ttagtatgag tgtcgtgcag cc#tccaggac    120cccccctccc gggagagcca tagtggtctg cggaaccggt gagtacaccg ga#attgccag    180gacgaccggg tcctttcttg gataaacccg ctcaatgcct ggagatttgg gc#gtgccccc    240gcaagactgc tagccgagta gtgttgggtc gcgaaaggcc ttgtggtact gc#ctgatagg    300gtgcttgcga gtgccccggg aggtctcgta gaccgtgcac catgagcacg aa#tcctaaac    360ctcaaagaaa aaccaaacgt aacaccaacc gtcgcccaca ggacgtcaag tt#cccgggtg    420gcggtcagat cgttggtgga gtttacttgt tgccgcgcag gggccctaga tt#gggtgtgc    480gcgcgacgag gaagacttcc gagcggtcgc aacctcgagg tagacgtcag cc#tatcccca    540aggcacgtcg gcccgagggc aggacctggg ctcagcccgg gtacccttgg cc#cctctatg    600gcaatgaggg ttgcgggtgg gcgggatggc tcctgtctcc ccgtggctct cg#gcctagct    660ggggccccac agacccccgg cgtaggtcgc gcaatttggg taaggtcatc ga#taccctta    720cgtgcggctt cgccgacctc atggggtaca taccgctcgt cggcgcccct ct#tggaggcg    780ctgccagggc cctggcgcat ggcgtccggg ttctggaaga cggcgtgaac ta#tgcaacag    840ggaaccttcc tggttgctct ttctctatct tccttctggc cctgctctct tg#cctgactg    900tgcccgcttc agcctaccaa gtgcgcaatt cctcggggct ttaccatgtc ac#caatgatt    960gccctaactc gagtgttgtg tacgaggcgg ccgatgccat cctgcacact cc#ggggtgtg   1020tcccttgcgt tcgcgagggt aacgcctcga ggtgttgggt ggcggtgacc cc#cacggtgg   1080ccaccaggga cggcaaactc cccacaacgc agcttcgacg tcatatcgat ct#gcttgtcg   1140ggagcgccac cctctgctcg gccctctacg tgggggacct gtgcgggtct gt#ctttcttg   1200ttggtcaact gtttaccttc tctcccaggc accactggac gacgcaagac tg#caattgtt   1260ctatctatcc cggccatata acgggtcatc gcatggcatg gaatatgatg at#gaactggt   1320cccctacggc agcgttggtg gtagctcagc tgctccgaat cccacaagcc at#catggaca   1380tgatcgctgg cgcccactgg ggagtcctgg cgggcataaa gtatttctcc at#ggtgggga   1440actgggcgaa ggtcctggta gtgctgctgc tatttgccgg cgtcgacgcg ga#aacccacg   1500tcaccggggg aaatgccggc cgcaccacgg ctgggcttgt tggtctcctt ac#accaggcg   1560ccaagcagaa catccaactg atcaacacca acggcagttg gcacatcaat ag#cacggcct   1620tgaactgcaa tgaaagcctt aacaccggct ggttagcagg gctcttctat ca#gcacaaat   1680tcaactcttc aggctgtcct gagaggttgg ccagctgccg acgccttacc ga#ttttgccc   1740agggctgggg tcctatcagt tatgccaacg gaagcggcct cgacgaacgc cc#ctactgct   1800ggcactaccc tccaagacct tgtggcattg tgcccgcaaa gagcgtgtgt gg#cccggtat   1860attgcttcac tcccagcccc gtggtggtgg gaacgaccga caggtcgggc gc#gcctacct   1920acagctgggg tgcaaatgat acggatgtct tcgtccttaa caacaccagg cc#accgctgg   1980gcaattggtt cggttgtacc tggatgaact caactggatt caccaaagtg tg#cggagcgc   2040ccccttgtgt catcggaggg gtgggcaaca acaccttgct ctgccccact ga#ttgcttcc   2100gcaaatatcc ggaagccaca tactctcggt gcggctccgg tcccaggatt ac#acccaggt   2160gcatggtcga ctacccgtat aggctttggc actatccttg taccatcaat ta#caccatat   2220tcaaagtcag gatgtacgtg ggaggggtcg agcacaggct ggaagcggcc tg#caactgga   2280cgcggggcga acgctgtgat ctggaagaca gggacaggtc cgagctcagc cc#gttgctgc   2340tgtccaccac acagtggcag gtccttccgt gttctttcac gaccctgcca gc#cttgtcca   2400ccggcctcat ccacctccac cagaacattg tggacgtgca gtacttgtac gg#ggtagggt   2460caagcatcgc gtcctgggcc attaagtggg agtacgtcgt tctcctgttc ct#tctgcttg   2520cagacgcgcg cgtctgttcc tgcttgtgga tgatgttact catatcccaa gc#ggaggcgg   2580ctttggagaa cctcgtaata ctcaatgcag catccctggc cgggacgcat gg#tcttgtgt   2640ccttcctcgt gttcttctgc tttgcgtggt atctgaaggg taggtgggtg cc#cggagcgg   2700tctacgccct ctacgggatg tggcctctcc tcctgctcct gctggcgttg cc#tcagcggg   2760catacgcact ggacacggag gtggccgcgt cgtgtggcgg cgttgttctt gt#cgggttaa   2820tggcgctgac tctgtcgcca tattacaagc gctatatcag ctggtgcatg tg#gtggcttc   2880agtattttct gaccagagta gaagcgcaac tgcacgtgtg ggttcccccc ct#caacgtcc   2940ggggggggcg cgatgccgtc atcttactca cgtgtgtagt acacccggcc ct#ggtatttg   3000acatcaccaa actactcctg gccatcttcg gacccctttg gattcttcaa gc#cagtttgc   3060ttaaagtccc ctacttcgtg cgcgttcaag gccttctccg gatctgcgcg ct#agcgcgga   3120agatagccgg aggtcattac gtgcaaatgg ccatcatcaa gttaggggcg ct#tactggca   3180cctgtgtgta taaccatctc gctcctcttc gagactgggc gcacaacggc ct#gcgagatc   3240tggccgtggc tgtggaacca gtcgtcttct cccgaatgga gaccaagctc at#cacgtggg   3300gggcagatac cgccgcgtgc ggtgacatca tcaacggctt gcccgtctct gc#ccgtaggg   3360gccaggagat actgcttggg ccagccgacg gaatggtctc caaggggtgg ag#gttgctgg   3420cgcccatcac ggcgtacgcc cagcagacga gaggcctcct agggtgtata at#caccagcc   3480tgactggccg ggacaaaaac caagtggagg gtgaggtcca gatcgtgtca ac#tgctaccc   3540agaccttcct ggcaacgtgc atcaatgggg tatgctggac tgtctaccac gg#ggccggaa   3600cgaggaccat cgcatcaccc aagggtcctg tcatccagac gtataccaat gt#ggatcaag   3660acctcgtggg ctggcccgct cctcaaggtt cccgctcatt gacaccctgc ac#ctgcggct   3720cctcggacct ttacctggtc acgaggcacg ccgatgtcat tcccgtgcgc cg#gcgaggtg   3780atagcagggg tagcctgctt tcgccccggc ccatttccta cttgaaaggc tc#ctcggggg   3840gtccgctgtt gtgccccacg ggacacgccg tgggcctatt cagggccgcg gt#gtgcaccc   3900gtggagtggc taaggcggtg gactttatcc ctgtggagaa cctagagaca ac#catgagat   3960ccccggtgtt cacggacaac tcctctccac cagcagtgcc ccagagcttc ca#ggtggccc   4020acctgcatgc tcccaccggc agcggtaaga gcaccaaggt cccggctgcg ta#cgcagcca   4080agggctacaa ggtgttggtg ctcaacccct ctgttgctgc aacactgggc tt#tggtgctt   4140acatgtccaa ggcccatggg gttgatccta atatcaggac cggggtgaga ac#aattacca   4200ctggcagccc catcacgtac tccacctacg gcaagttcct tgccgacgcc gg#gtgctcag   4260gaggtgctta tgacataata atttgtgacg agtgccactc cacggatgcc ac#atccatct   4320cgggcatcgg cactgtcctt gaccaagcag agactgcggg ggcgagactg gt#tgtgctcg   4380ccactgctac ccctccgggc tccgtcactg tgtcccatcc taacatcgag ga#ggttgctc   4440tgtccaccac cggagagatc cccttttacg gcaaggctat ccccctcgag gt#gatcaagg   4500ggggaagaca tctcatcttc tgccactcaa agaagaagtg cgacgagctc gc#cgcgaagc   4560tggtcgcatt gggcatcaat gccgtggcct actaccgcgg tcttgacgtg tc#tgtcatcc   4620cgaccagcgg cgatgttgtc gtcgtgtcga ccgatgctct catgactggc tt#taccggcg   4680acttcgactc tgtgatagac tgcaacacgt gtgtcactca gacagtcgat tt#tagccttg   4740accctacctt taccattgag acaaccacgc tcccccagga tgctgtctcc ag#gactcaac   4800gccggggcag gactggcagg gggaagccag gcatctatag atttgtggca cc#gggggagc   4860gcccctccgg catgttcgac tcgtccgtcc tctgtgagtg ctatgacgcg gg#ctgtgctt   4920ggtatgagct cacgcccgcc gagactacag ttaggctacg agcgtacatg aa#caccccgg   4980ggcttcccgt gtgccaggac catcttggat tttgggaggg cgtctttacg gg#cctcactc   5040atatagatgc ccactttcta tcccagacaa agcagagtgg ggagaacttt cc#ttacctgg   5100tagcgtacca agccaccgtg tgcgctaggg ctcaagcccc tcccccatcg tg#ggaccaga   5160tgcggaagtg tttgatccgc cttaaaccca ccctccatgg gccaacaccc ct#gctataca   5220gactgggcgc tgttcagaat gaagtcaccc tgacgcaccc aatcaccaaa ta#catcatga   5280catgcatgtc ggccgacctg gaggtcgtca cgagcacctg ggtgctcgtt gg#cggcgtcc   5340tggctgctct ggccgcgtat tgcctgtcaa caggctgcgt ggtcatagtg gg#caggatcg   5400tcttgtccgg gaagccggca attatacctg acagggaggt tctctaccag ga#gttcgatg   5460agatggaaga gtgctctcag cacttaccgt acatcgagca agggatgatg ct#cgctgagc   5520agttcaagca gaaggccctc ggcctcctgc agaccgcgtc ccgccatgca ga#ggttatca   5580cccctgctgt ccagaccaac tggcagaaac tcgaggtctt ttgggcgaag ca#catgtgga   5640atttcatcag tgggatacaa tacttggcgg gcctgtcaac gctgcctggt aa#ccccgcca   5700ttgcttcatt gatggctttt acagctgccg tcaccagccc actaaccact gg#ccaaaccc   5760tcctcttcaa catattgggg gggtgggtgg ctgcccagct cgccgccccc gg#tgccgcta   5820ccgcctttgt gggcgctggc ttagctggcg ccgcactcga cagcgttgga ct#ggggaagg   5880tcctcgtgga cattcttgca ggctatggcg cgggcgtggc gggagctctt gt#ggcattca   5940agatcatgag cggtgaggtc ccctccacgg aggacctggt caatctgctg cc#cgccatcc   6000tctcacctgg agcccttgca gtcggtgtgg tctttgcatc aatactgcgc cg#gcgtgttg   6060gcccgggcga gggggcagtg caatggatga accggctaat agccttcgcc tc#ccggggga   6120accatgtttc ccccacacac tacgtgccgg agagcgatgc agccgcccgc gt#cactgcca   6180tactcagcag cctcactgta acccagctcc tgaggcgact gcatcagtgg at#aagctcgg   6240agtgtaccac tccatgctcc ggttcctggc taagggacat ctgggactgg at#atgcgagg   6300tgctgagcga ctttaagacc tggctgaaag ccaagctcat gccacaactg cc#tgggattc   6360cctttgtgtc ctgccagcgc gggtataggg gggtctggcg aggagacggc at#tatgcaca   6420ctcgctgcca ctgtggagct gagatcactg gacatgtcaa aaacgggacg at#gaggatcg   6480tcggtcctag gacctgcaag aacatgtgga gtgggacgtt cttcattaat gc#ctacacca   6540cgggcccctg tactcccctt cctgcgccga actataagtt cgcgctgtgg ag#ggtgtctg   6600cagaggaata cgtggagata aggcgggtgg gggacttcca ctacgtatcg gg#catgacta   6660ctgacaatct caaatgcccg tgccagatcc catcgcccga atttttcaca ga#attggacg   6720gggtgcgcct acataggttt gcgccccctt gcaagccctt gctgcgggag ga#ggtatcat   6780tcagagtagg actccacgag tacccggtgg ggtcgcaatt accttgcgag cc#cgaaccgg   6840acgtagccgt gttgacgtcc atgctcactg atccctccca tataacagca ga#ggcggccg   6900ggagaaggtt ggcgagaggg tcaccccctt ctatggccag ctcctcggct ag#ccagctgt   6960ccgctccatc tctcaaggca acttgcaccg ccaaccatga ctcccctgac gc#cgagctca   7020tagaggctaa cctcctgtgg aggcaggaga tgggcggcaa catcaccagg gt#tgagtcag   7080agaacaaagt ggtgattctg gactccttcg atccgcttgt ggcagaggag ga#tgagcggg   7140aggtctccgt acccgcagaa attctgcgga agtctcggag attcgcccca gc#cctgcccg   7200tctgggcgcg gccggactac aaccccctgc tagtagagac gtggaaaaag cc#tgactacg   7260aaccacctgt ggtccatggc tgcccgctac cacctccacg gtcccctcct gt#gcctccgc   7320ctcggaaaaa gcgtacggtg gtcctcaccg aatcaaccct acctactgcc tt#ggccgagc   7380ttgccaccaa aagttttggc agctcctcaa cttccggcat tacgggcgac aa#tacgacaa   7440catcctctga gcccgcccct tctggctgcc cccccgactc cgacgttgag tc#ctattctt   7500ccatgccccc cctggagggg gagcctgggg atccggatct cagcgacggg tc#atggtcga   7560cggtcagtag tggggccgac acggaagatg tcgtgtgctg ctcaatgtct ta#ttcctgga   7620caggcgcact cgtcaccccg tgcgctgcgg aggaacaaaa actgcccatc aa#cgcactga   7680gcaactcgtt gctacgccat cacaatctgg tgtattccac cacttcacgc ag#tgcttgcc   7740aaaggaagaa gaaagtcaca tttgacagac tgcaagttct ggacagccat ta#ccaggacg   7800tgctcaagga ggtcaaagca gcggcgtcaa aagtgaaggc taacttgcta tc#cgtagagg   7860aagcttgcag cctggcgccc ccacattcag ccaaatccaa gtttggctat gg#ggcaaaag   7920acgtccgttg ccatgccaga aaggccgtag cccacatcaa ctccgtgtgg aa#agaccttc   7980tggaagacag tgtaacacca atagacacta ccatcatggc caagaacgag gt#tttctgcg   8040ttcagcctga gaaggggggt cgtaagccag ctcgtctcat cgtgttcccc ga#cctgggcg   8100tgcgcgtgtg cgagaagatg gccctgtacg acgtggttag caagctcccc tt#ggccgtga   8160tgggaagctc ctacggattc caatactcac caggacagcg ggttgaattc ct#cgtgcaag   8220cgtggaagtc caagaagacc ccgatggggc tctcgtatga tacccgctgt tt#tgactcca   8280cagtcactga gagcgacatc cgtacggagg aggcaattta ccaatgttgt ga#cctggacc   8340cccaagcccg cgtggccatc aagtccctca ctgagaggct ttatgttggg gg#ccctctta   8400ctaattcaag gggggaaaac tgcggctacc gcaggtgccg cgcgagcaga gt#actgacaa   8460ctagctgtgg taacaccctc actcgctaca tcaaggcccg ggcagcctgt cg#agccgcag   8520ggctccagga ctgcaccatg ctcgtgtgtg gcgacgactt agtcgttatc tg#tgaaagtg   8580cgggggtcca ggaggacgcg gcgagcctga gagccttcac ggaggctatg ac#caggtact   8640ccgccccccc cggggacccc ccacaaccag aatacgactt ggagcttata ac#atcatgct   8700cctccaacgt gtcagtcgcc cacgacggcg ctggaaagag ggtctactac ct#tacccgtg   8760accctacaac ccccctcgcg agagccgcgt gggagacagc aagacacact cc#agtcaatt   8820cctggctagg caacataatc atgtttgccc ccacactgtg ggcgaggatg at#actgatga   8880cccacttctt tagcgtcctc atagccaggg atcagcttga acaggctctc aa#ctgcgaga   8940tctacggagc ctgctactcc atagaaccac tggatctacc tccaatcatt ca#aagactcc   9000atggcctcag cgcattttca ctccacagtt actctccagg tgaaattaat ag#ggtggccg   9060catgcctcag aaaacttggg gtcccgccct tgcgagcttg gagacaccgg gc#ctggagcg   9120tccgcgctag gcttctggcc agaggaggca aggctgccat atgtggcaag ta#cctcttca   9180actgggcagt aagaacaaag ctcaaactca ctccgataac ggccgctggc cg#gctggact   9240tgtccggctg gttcacggct ggctacagcg ggggagacat ttatcacagc gt#gtctcatg   9300cccggccccg ctggttctgg ttttgcctac tcctgcttgc tgcaggggta gg#catctacc   9360tcctccccaa ccgatgaaga ttgggctaac cactccaggc caataggcca tt#ccct       9416 <210> SEQ ID NO 14 <211> LENGTH: 3182 <212> TYPE: DNA<213> ORGANISM: Artificial Sequence <220> FEATURE:<223> OTHER INFORMATION: Hepatitis B virus sequenc #e <400> SEQUENCE: 14aattccacaa ccttccacca aactctgcaa gatcccagag tgagaggcct gt#atttccct     60gctggtggct ccagttcagg aacagtaaac cctgttctga ctactgcctc tc#ccttatcg    120tcaatcttct cgaggattgg ggaccctgcg ctgaacatgg agaacatcac at#caggattc    180ctaggacccc ttctcgtgtt acaggcgggg tttttcttgt tgacaagaat cc#tcacaata    240ccgcagagtc tagactcgtg gtggacttct ctcaattttc tagggggaac ta#ccgtgtgt    300cttggccaaa attcgcagtc cccaacctcc aatcactcac caacctcttg tc#ctccaact    360tgtcctggtt atcgctggat gtgtctgcgg cgttttatca tcttcctctt ca#tcctgctg    420ctatgcctca tcttcttgtt ggttcttctg gactatcaag gtatgttgcc cg#tttgtcct    480ctaattccag gatcctcaac aaccagcacg ggaccatgcc ggacctgcat ga#ctactgct    540caaggaacct ctatgtatcc ctcctgttgc tgtaccaaac cttcggacgg aa#attgcacc    600tgtattccca tcccatcatc ctgggctttc ggaaaattcc tatgggagtg gg#cctcagcc    660cgtttctcct ggctcagttt actagtgcca tttgttcagt ggttcgtagg gc#tttccccc    720actgtttggc tttcagttat atggatgatg tggtattggg ggccaagtct gt#acagcatc    780ttgagtccct ttttaccgct gttaccaatt ttcttttgtc tttgggtata ca#tttaaacc    840ctaacaaaac aaagagatgg ggttactctc taaattttat gggttatgtc at#tggatgtt    900atgggtcctt gccacaagaa cacatcatac aaaaaatcaa agaatgtttt ag#aaaacttc    960ctattaacag gcctattgat tggaaagtat gtcaacgaat tgtgggtctt tt#gggttttg   1020ctgccccttt tacacaatgt ggttatcctg cgttgatgcc tttgtatgca tg#tattcaat   1080ctaagcaggc tttcactttc tcgccaactt acaaggcctt tctgtgtaaa ca#atacctga   1140acctttaccc cgttgcccgg caacggccag gtctgtgcca agtgtttgct ga#cgcaaccc   1200ccactggctg gggcttggtc atgggccatc agcgcatgcg tggaaccttt tc#ggctcctc   1260tgccgatcca tactgcggaa ctcctagccg cttgttttgc tcgcagcagg tc#tggagcaa   1320acattatcgg gactgataac tctgttgtcc tatcccgcaa atatacatcg tt#tccatggc   1380tgctaggctg tgctgccaac tggatcctgc gcgggacgtc ctttgtttac gt#cccgtcgg   1440cgctgaatcc tgcggacgac ccttctcggg gtcgcttggg actctctcgt cc#ccttctcc   1500gtctgccgtt ccgaccgacc acggggcgca cctctcttta cgcggactcc cc#gtctgtgc   1560cttctcatct gccggaccgt gtgcacttcg cttcacctct gcacgtcgca tg#gagaccac   1620cgtgaacgcc caccaaatat tgcccaaggt cttacataag aggactcttg ga#ctctcagc   1680aatgtcaacg accgaccttg aggcatactt caaagactgt ttgtttaaag ac#tgggagga   1740gttgggggag gagattaggt taaaggtctt tgtactagga ggctgtaggc at#aaattggt   1800ctgcgcacca gcaccatgca actttttcac ctctgcctaa tcatctcttg tt#catgtcct   1860actgttcaag cctccaagct gtgccttggg tggctttggg gcatggacat cg#acccttat   1920aaagaatttg gagctactgt ggagttactc tcgtttttgc cttctgactt ct#ttccttca   1980gtacgagatc ttctagatac cgcctcagct ctgtatcggg aagccttaga gt#ctcctgag   2040cattgttcac ctcaccatac tgcactcagg caagcaattc tttgctgggg gg#aactaatg   2100actctagcta cctgggtggg tgttaatttg gaagatccag cgtctagaga cc#tagtagtc   2160agttatgtca acactaatat gggcctaaag ttcaggcaac tcttgtggtt tc#acatttct   2220tgtctcactt ttggaagaga aacagttata gagtatttgg tgtctttcgg ag#tgtggatt   2280cgcactcctc cagcttatag accaccaaat gcccctatcc tatcaacact tc#cggagact   2340actgttgtta gacgacgagg caggtcccct agaagaagaa ctccctcgcc tc#gcagacga   2400aggtctcaat cgccgcgtcg cagaagatct caatctcggg aatctcaatg tt#agtattcc   2460ttggactcat aaggtgggga actttactgg gctttattct tctactgtac ct#gtctttaa   2520tcctcattgg aaaacaccat cttttcctaa tatacattta caccaagaca tt#atcaaaaa   2580atgtgaacag tttgtaggcc cactcacagt taatgagaaa agaagattgc aa#ttgattat   2640gcctgccagg ttttatccaa aggttaccaa atatttacca ttggataagg gt#attaaacc   2700ttattatcca gaacatctag ttaatcatta cttccaaact agacactatt ta#cacactct   2760atggaaggcg ggtatattat ataagagaga aacaacacat agcgcctcat tt#tgtgggtc   2820accatattct tgggaacaag atctacagca tggggcagaa tctttccacc ag#caatcctc   2880tgggattctt tcccgaccac cagttggatc cagccttcag agcaaacacc gc#aaatccag   2940attgggactt caatcccaac aaggacacct ggccagacgc caacaaggta gg#agctggag   3000cattcgggct gggtttcacc ccaccgcacg gaggcctttt ggggtggagc cc#tcaggctc   3060agggcatact acaaactttg ccagcaaatc cgcctcctgc ctccaccaat cg#ccagtcag   3120gaaggcagcc taccccgctg tctccacctt tgagaaacac tcatcctcag gc#catgcagt   3180 gg                   #                  #                   #            3182 <210> SEQ ID NO 15<211> LENGTH: 7478 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence<220> FEATURE: <223> OTHER INFORMATION: Hepatitis A virus sequenc #e<400> SEQUENCE: 15ttcaagaggg gtctccggag gtttccggag cccctcttgg aagtccatgg tg#aggggact     60tgatacctca ccgccgtttg cctaggctat aggctaaatt tccctttccc tg#tccctccc    120ttatttccct ttgttttgct tgtaaatatt aattcctgca ggttcagggt tc#tttaatct    180gtttctctat aagaacactc aattttcacg ctttctgtct tctttcttcc ag#ggctctcc    240ccttgcccta ggctctggcc gttgcgcccg gcggggtcaa ctccatgatt ag#catggagc    300tgtaggagtc taaattgggg acgcagatgt ttgggacgtc accttgcagt gt#taacttgg    360ctctcatgaa cctctttgat cttccacaag gggtaggcta cgggtgaaac ct#cttaggct    420aatacttcta tgaagagatg ctttggatag ggtaacagcg gcggatattg gt#gagttgtt    480aagacaaaaa ccattcaacg ccggaggact ggctctcatc cagtggatgc at#tgagtgga    540ttgattgtca gggctgtctc taggtttaat ctcagacctc tctgtgctta gg#gcaaacac    600catttggcct taaatgggat cctgtgagag ggggtccctc cattgacagc tg#gactgttc    660tttggggcct tatgtggtgt ttgcctctga ggtactcagg ggcatttagg tt#tttcctca    720ttcttaaaca ataatgaata tgtccaaaca aggaattttc cagactgttg gg#agtggcct    780tgaccacatc ctgtctttgg cagatattga ggaagagcaa atgattcagt cc#gttgatag    840gactgcagtg actggagctt cttacttcac ttctgtggac caatcttcag tt#catactgc    900tgaggttggc tcacatcaaa ttgaaccttt gaaaacctct gttgataaac ct#ggttctaa    960gaaaactcag ggggaaaagt ttttcctgat tcattctgct gattggctca ct#acacatgc   1020tctctttcat gaagttgcaa aattggatgt ggtgaaacta ctgtataatg ag#cagtttgc   1080cgtccaaggt ttgttgagat accatacata tgcaagattt ggcattgaga tt#caagttca   1140gataaatccc acaccctttc agcaaggagg actaatttgt gccatggttc ct#ggtgacca   1200aagttatggt tcaatagcat ccttgactgt ttatcctcat ggtctgttaa at#tgcaatat   1260caacaatgta gttagaataa aggttccatt tatttatact agaggtgctt at#cattttaa   1320agatccacag tacccagttt gggaattgac aatcagagtt tggtcagagt tg#aatattgg   1380aacaggaact tcagcttaca cttcactcaa tgttttagct aggtttacag at#ttggagtt   1440gcatggatta actcctcttt ctacacagat gatgagaaat gaatttaggg tc#agtactac   1500tgaaaatgtt gtaaatttgt caaattatga agatgcaagg gcaaaaatgt ct#tttgcttt   1560ggatcaggaa gattggaagt ctgatccttc ccaaggtggt ggaattaaaa tt#actcattt   1620tactacctgg acatccattc caaccttagc tgctcagttt ccatttaatg ct#tcagattc   1680agttggacaa caaattaaag ttattccagt ggacccatac tttttccaaa tg#acaaacac   1740taatcctgat caaaaatgta taactgcctt ggcctctatt tgtcagatgt tc#tgcttttg   1800gaggggagat cttgtttttg attttcaggt ttttccaacc aaatatcatt ca#ggtagact   1860gttgttttgt tttgttcctg ggaatgagtt aatagatgtt actggaatta ca#ttaaaaca   1920ggcaactact gctccttgtg cagtgatgga cattacagga gtgcagtcaa cc#ttgagatt   1980tcgtgttcct tggatttctg atacacctta tcgagtgaat aggtacacga ag#tcagcaca   2040tcaaaaaggt gagtacactg ccattgggaa gcttattgtg tattgttata ac#agactgac   2100ttctccttct aatgttgcct ctcatgttag agttaatgtt tatctttcag ca#attaattt   2160ggaatgtttt gctcctcttt accatgctat ggatgttact acacaggttg ga#gatgattc   2220aggaggtttc tcaacaacag tttctacaga gcagaatgtt cctgatcccc aa#gttgggat   2280aacaaccatg agggatttaa aaggaaaagc caatagggga aagatggatg tt#tcaggagt   2340gcaagcacct cgtgggagct atcagcaaca attgaacgat ccagttttag ca#aagaaagt   2400acctgagaca tttcctgaat tgaagcctgg agagtccaga catacatcag at#cacatgtc   2460tatttataaa ttcatgggaa ggtctcattt tttgtgcact tttactttca at#tcaaataa   2520taaagagtac acatttccaa taaccctgtc ttcgacttct aatcctcctc at#ggtttacc   2580atcaacatta aggtggttct tcaatttgtt tcagttgtat agaggaccat tg#gatttaac   2640aattataatc acaggagcca ctgatgtgga tggtatggcc tggtttactc ca#gtgggcct   2700tgctgtcgac ccttgggtgg aaaaggagtc agctttgtct attgattata aa#actgccct   2760tggagctgtt agatttaata caagaagaac aggaaacatt caaattagat tg#ccgtggta   2820ttcttatttg tatgccgtgt ctggagcact ggatggcttg ggggataaga ca#gattctac   2880atttggattg tttctattcg agattgcaaa ttacaatcat tctgatgaat at#ttgtcctt   2940cagttgttat ttgtctgtca cagagcaatc agagttctat tttcctagag ct#ccattaaa   3000ttcaaatgct atgttgtcca ctgaatccat gatgagtaga attgcagctg ga#gacttgga   3060gtcatcagtg gatgatccca gatcagagga ggatagaaga tttgagagtc at#atagaatg   3120taggaaacca tacaaagaat tgagactgga ggttgggaaa caaagactca aa#tatgctca   3180ggaagagtta tcaaatgaag tgcttccacc tcctaggaaa atgaaggggt ta#ttttcaca   3240agctaaaatt tctctttttt atactgagga gcatgaaata atgaagtttt ct#tggagagg   3300agtgactgct gatactaggg ctttgagaag atttggattc tctctggctg ct#ggtagaag   3360tgtgtggact cttgaaatgg atgctggagt tcttactgga agattgatca ga#ttgaatga   3420tgagaaatgg acagaaatga aggatgataa gattgtttca ttaattgaaa ag#ttcacaag   3480caataaatat tggtctaaag tgaattttcc acatggaatg ttggatcttg aa#gaaattgc   3540tgccaattct aaggattttc caaatatgtc tgagacagat ttgtgtttcc tg#ttacattg   3600gctaaatcca aagaaaatca atttagcaga tagaatgctt ggattgtctg ga#gtgcagga   3660aattaaggaa cagggtgttg gactgatagc agagtgtaga actttcttgg at#tctattgc   3720tgggactttg aaatctatga tgtttgggtt tcatcattct gtgactgttg aa#attataaa   3780tactgtgctt tgttttgtta agagtggaat cctgctttat gtcatacaac aa#ttgaacca   3840agatgaacac tctcacataa ttggtttgtt gagagttatg aattatgcag at#attggctg   3900ttcagttatt tcatgtggta aagttttttc caaaatgtta gaaacagttt tt#aattggca   3960aatggattct agaatgatgg agctgaggac tcagagcttc tctaattggt ta#agagatat   4020ttgttcagga attactattt ttaaaagttt taaggatgcc atatattggt ta#tatacaaa   4080attgaaggat ttttatgaag taaattatgg caagaaaaag gatattctta at#attctcaa   4140agataatcag caaaaaatag aaaaagccat tgaagaagca gacaattttt gc#attttgca   4200aattcaagat gtagagaaat ttgatcagta tcagaaaggg gttgatttaa ta#caaaagct   4260gagaactgtc cattcaatgg cgcaagttga ccccaatttg ggggttcatt tg#tcacctct   4320cagagattgc atagcaagag tccaccaaaa gctcaagaat cttggatcta ta#aatcaggc   4380catggtaaca agatgtgagc cagttgtttg ctatttgtat ggcaaaagag gg#ggagggaa   4440aagcttgact tcaattgcat tggcaaccaa aatttgtaaa cactatggtg tt#gaacctga   4500gaaaaatatt tacaccaaac ctgtggcctc agattattgg gatggatata gt#ggacaatt   4560agtttgcatt attgatgata ttggccaaaa cacaacagat gaagattggt ca#gatttttg   4620tcaattagtg tcaggatgcc caatgagatt gaatatggct tctctagagg ag#aagggcag   4680acatttttcc tctcctttta taatagcaac ttcaaattgg tcaaatccaa gt#ccaaaaac   4740agtttatgtt aaggaagcaa ttgatcgtag gcttcatttt aaggttgaag tt#aaacctgc   4800ttcatttttt aaaaatcctc acaatgatat gttgaatgtt aatttggcca aa#acaaatga   4860tgcaattaag gacatgtctt gtgttgattt aataatggat ggacacaata tt#tcattgat   4920ggatttactt agttccttag tgatgacagt tgaaattagg aaacagaata tg#agtgaatt   4980catggagttg tggtctcagg gaatttcaga tgatgacaat gatagtgcag tg#gctgagtt   5040tttccagtct tttccatctg gtgaaccatc aaattggaag ttatctagtt tt#ttccaatc   5100tgtcactaat cacaagtggg ttgctgtggg agctgcagtt ggcattcttg ga#gtgcttgt   5160gggaggatgg tttgtgtata agcatttttc ccgcaaagag gaagaaccaa tt#ccagctga   5220aggggtttat catggcgtga ctaagcccaa acaagtgatt aaattggatg ca#gatccagt   5280agagtcccag tcaactctag aaatagcagg attagttagg aaaaatctgg tt#cagtttgg   5340agttggtgag aaaaatggat gtgtgagatg ggtcatgaat gccttaggag tg#aaggatga   5400ttggttgtta gtaccttctc atgcttataa atttgaaaag gattatgaaa tg#atggagtt   5460ttacttcaat agaggtggaa cttactattc aatttcagct ggtaatgttg tt#attcaatc   5520tttagatgtg ggatttcaag atgttgtttt aatgaaggtt cctacaattc cc#aagtttag   5580agatattact caacacttta ttaagaaagg agatgtgcct agagccttaa at#cgcttggc   5640aacattagtg acaaccgtta atggaactcc tatgttaatt tctgagggac ca#ttaaagat   5700ggaagaaaaa gccacttatg ttcataagaa gaatgatggt actacagttg at#ttgactgt   5760agatcaggca tggagaggaa aaggtgaagg tcttcctgga atgtgtggtg gg#gccctagt   5820gtcatcaaat cagtccatac agaatgcaat tttgggtatt catgttgctg ga#ggaaattc   5880aattcttgtg gcaaagctgg ttactcaaga aatgtttcaa aacattgata ag#aaaattga   5940aagtcagaga ataatgaaag tggaatttac tcaatgttca atgaatgtag tc#tccaaaac   6000gctttttaga aagagtccca ttcatcacca cattgataaa accatgatta at#tttcctgc   6060agctatgcct ttctctaaag ctgaaattga tccaatggct atgatgttgt cc#aaatattc   6120attacctatt gtggaggaac cagaggatta caaggaagct tcagtttttt at#caaaacaa   6180aatagtaggc aagactcagc tagttgatga ctttttagat cttgatatgg ct#attacagg   6240ggctccaggc attgatgcta tcaatatgga ttcatctcct gggtttcctt at#gttcaaga   6300aaaattgacc aaaagagatt taatttggtt ggatgaaaat ggtttgctgt ta#ggagttca   6360cccaagattg gcccagagaa ttttatttaa tactgtcatg atggaaaatt gt#tctgactt   6420agatgttgtt tttacaactt gtccaaaaga tgaattgaga ccattagaga aa#gttttgga   6480atcaaaaaca agagccattg atgcttgtcc tttggattat acaattctat gt#cgaatgta   6540ttggggtcca gctatcagtt atttccattt gaatccaggg tttcacacag gt#gttgctat   6600tggcatagat cctgatagac agtgggatga attatttaaa acaatgataa ga#tttggaga   6660tgttggtctt gatttagatt tctctgcttt tgatgccagt cttagtccat tt#atgattag   6720ggaagcaggt agaatcatga gtgaattatc tggaacacca tctcattttg ga#acagctct   6780tatcaatact atcatttatt ctaaacatct gctgtacaac tgttgttatc at#gtttgtgg   6840ttcaatgcct tctgggtctc cttgcacagc tttgttgaat tcaattatta at#aatattaa   6900tctgtattat gtgttttcta aaatatttgg aaagtctcca gttttctttt gt#caagcttt   6960gaggatcctt tgttacggag atgatgtttt gatagttttt tccagagatg tt#caaattga   7020caatcttgac ttgattggac agaaaattgt agatgagttc aaaaaacttg gc#atgacagc   7080cacctcagct gataaaaatg tgcctcaact gaagccagtt tcagaattga ct#tttctcaa   7140aagatctttc aatttggtgg aggatagaat tagacctgca atttcagaaa ag#acaatttg   7200gtctttgatg gcttggcaga gaagtaacgc tgagtttgag cagaatttag aa#aatgctca   7260gtggtttgct tttatgcatg gctatgagtt ctatcagaaa ttttattatt tt#gttcagtc   7320ctgtttggag aaagagatga tagaatatag acttaaatct tatgattggt gg#agaatgag   7380attttatgac cagtgtttca tttgtgacct ttcatgattt gtttaaacaa at#tttcttac   7440 tctttctgag gtttgtttat ttcttttgtc cgctaact      #                   #   7478

What is claimed is:
 1. An immunogenic composition comprising a viralantigen and ribavirin for co-administration thereof.
 2. The immunogeniccomposition of claim 1, wherein said viral antigen is a hepatitisantigen.
 3. The immunogenic composition of claim 1, wherein said viralantigen is a hepatitis C viral antigen.
 4. The immunogenic compositionof claim 1, wherein said viral antigen comprises NS3.
 5. The immunogeniccomposition of claim 1, wherein said viral antigen is a hepatitis Bviral antigen.
 6. The immunogenic composition of claim 1, wherein theamount of ribavirin is at least 0.25 mg.
 7. The immunogenic compositionof claim 1, wherein the amount of ribavirin is between about 0.25 mg and100 mg.
 8. The immunogenic composition of claim 1, wherein the amount ofribavirin is between about 0.25 mg and 25 mg.
 9. The immunogeniccomposition of claim 1, wherein the amount of ribavirin is between about0.25 mg and 1 mg.
 10. The immunogenic composition of claim 1, whereinthe amount of ribavirin is at least 0.1 mg ribavirin per kg body weightof a subject receiving said composition.
 11. The immunogenic compositionof claim 1, wherein the amount of ribavirin is between about 0.1 mgribavirin to about 1.0 mg ribavirin per kg body weight of a subjectreceiving said composition.
 12. The immunogenic composition of claim 1,wherein the amount of ribavirin is between about 1.1 mg ribavirin toabout 2.0 mg ribavirin per kg body weight of a subject receiving saidcomposition.
 13. The immunogenic composition of claim 1, wherein theamount of ribavirin is between about 2.1 mg ribavirin to about 3.0 mgribavirin per kg body weight of a subject receiving said composition.14. The immunogenic composition of claim 1, wherein the amount ofribavirin is between about 3.1 mg ribavirin to about 4.0 mg ribavirinper kg body weight of a subject receiving said composition.
 15. Theimmunogenic composition of claim 2, wherein the amount of ribavirin isat least 0.25 mg.
 16. The immunogenic composition of claim 2, whereinthe amount of ribavirin is between about 0.25 mg and 100 mg.
 17. Theimmunogenic composition of claim 2, wherein the amount of ribavirin isbetween about 0.25 mg and 25 mg.
 18. The immunogenic composition ofclaim 2, wherein the amount of ribavirin is between about 0.25 mg and 1mg.
 19. The immunogenic composition of claim 2, wherein the amount ofribavirin is at least 0.1 mg ribavirin per kg body weight of a subjectreceiving said composition.
 20. The immunogenic composition of claim 2,wherein the amount of ribavirin is between about 0.1 mg ribavirin toabout 1.0 mg ribavirin per kg body weight of a subject receiving saidcomposition.
 21. The immunogenic composition of claim 2, wherein theamount of ribavirin is between about 1.1 mg ribavirin to about 2.0 mgribavirin per kg body weight of a subject receiving said composition.22. The immunogenic composition of claim 2, wherein the amount ofribavirin is between about 2.1 mg ribavirin to about 3.0 mg ribavirinper kg body weight of a subject receiving said composition.
 23. Theimmunogenic composition of claim 2, wherein the amount of ribavirin isbetween about 3.1 mg ribavirin to about 4.0 mg ribavirin per kg bodyweight of a subject receiving said composition.
 24. The immunogeniccomposition of claim 3, wherein the amount of ribavirin is at least 0.25mg.
 25. The immunogenic composition of claim 3, wherein the amount ofribavirin is between about 0.25 mg and 100 mg.
 26. The immunogeniccomposition of claim 3, wherein the amount of ribavirin is between about0.25 mg and 25 mg.
 27. The immunogenic composition of claim 3, whereinthe amount of ribavirin is between about 0.25 mg and 1 mg.
 28. Theimmunogenic composition of claim 3, wherein the amount of ribavirin isat least 0.1 mg ribavirin per kg body weight of a subject receiving saidcomposition.
 29. The immunogenic composition of claim 3, wherein theamount of ribavirin is between about 0.1 mg ribavirin to about 1.0 mgribavirin per kg body weight of a subject receiving said composition.30. The immunogenic composition of claim 3, wherein the amount ofribavirin is between about 1.1 mg ribavirin to about 2.0 mg ribavirinper kg body weight of a subject receiving said composition.
 31. Theimmunogenic composition of claim 3, wherein the amount of ribavirin isbetween about 2.1 mg ribavirin to about 3.0 mg ribavirin per kg bodyweight of a subject receiving said composition.
 32. The immunogeniccomposition of claim 3, wherein the amount of ribavirin is between about3.1 mg ribavirin to about 4.0 mg ribavirin per kg body weight of asubject receiving said composition.
 33. The immunogenic composition ofclaim 4, wherein the amount of ribavirin is at least 0.25 mg.
 34. Theimmunogenic composition of claim 4, wherein the amount of ribavirin isbetween about 0.25 mg and 100 mg.
 35. The immunogenic composition ofclaim 4, wherein the amount of ribavirin is between about 0.25 mg and 25mg.
 36. The immunogenic composition of claim 4, wherein the amount ofribavirin is between about 0.25 mg and 1 mg.
 37. The immunogeniccomposition of claim 4, wherein the amount of ribavirin is at least 0.1mg ribavirin per kg body weight of a subject receiving said composition.38. The immunogenic composition of claim 4, wherein the amount ofribavirin is between about 0.1 mg ribavirin to about 1.0 mg ribavirinper kg body weight of a subject receiving said composition.
 39. Theimmunogenic composition of claim 4, wherein the amount of ribavirin isbetween about 1.1 mg ribavirin to about 2.0 mg ribavirin per kg bodyweigh of a subject receiving said composition.
 40. The immunogeniccomposition of claim 4, wherein the amount of ribavirin is between about2.1 mg ribavirin to about 3.0 mg ribavirin per kg body weight of asubject receiving said composition.
 41. The immunogenic composition ofclaim 4, wherein the amount of ribavirin is between about 3.1 mgribavirin to about 4.0 mg ribavirin per kg body weight of a subjectreceiving said composition.
 42. The immunogenic composition of claim 5,wherein the amount of ribavirin is at least 0.25 mg.
 43. The immunogeniccomposition of claim 5, wherein the amount of ribavirin is between about0.25 mg and 100 mg.
 44. The immunogenic composition of claim 5, whereinthe amount of ribavirin is between about 0.25 mg and 25 mg.
 45. Theimmunogenic composition of claim 5, wherein the amount of ribavirin isbetween about 0.25 mg and 1 mg.
 46. The immunogenic composition of claim5, wherein the amount of ribavirin is at least 0.1 mg ribavirin per kgbody weight of a subject receiving said composition.
 47. The immunogeniccomposition of claim 5, wherein the amount of ribavirin is between about0.1 mg ribavirin to about 1.0 mg ribavirin per kg body weight of asubject receiving said composition.
 48. The immunogenic composition ofclaim 5, wherein the amount of ribavirin is between about 1.1 mgribavirin to about 2.0 mg ribavirin per kg body weight of a subjectreceiving said composition.
 49. The immunogenic composition of claim 5,wherein the amount of ribavirin is between about 2.1 mg ribavirin toabout 3.0 mg ribavirin per kg body weight of a subject receiving saidcomposition.
 50. The immunogenic composition of claim 5, wherein theamount of ribavirin is between about 3.1 mg ribavirin to about 4.0 mgribavirin per kg body weight of a subject receiving said composition.51. A method of making an immunogenic composition comprising a viralantigen and ribavirin for co-administration thereof comprising:providing a viral antigen; providing ribavirin; and combining said viralantigen and said ribavirin.
 52. The method of claim 51, wherein saidviral antigen is a hepatitis antigen.
 53. The method of claim 51,wherein said viral antigen is a hepatitis C viral antigen.
 54. Themethod of claim 51, wherein said viral antigen comprises NS3.
 55. Themethod of claim 51, wherein said viral antigen is a hepatitis B viralantigen.